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Review

Pipeline of Known Chemical Classes of Antibiotics

by
Cristina D'Urso De Souza Mendes
1,2,* and
Adelaide Maria De Souza Antunes
1,2
1
Graduate Program in Technology of Chemical and Biochemical Processes, Technology Center, Federal University of Rio de Janeiro (UFRJ), EQ/UFRJ, Centro de Tecnologia, Bloco E, Ilha do Fundão, Rio de Janeiro-RJ 21949-900, Brazil
2
Brazilian National Institute of Industrial Property, INPI/Rua Mayrink Veiga No. 9/19 andar, CEP 20090-910, Rio de Janeiro-RJ 20090-910, Brazil
*
Author to whom correspondence should be addressed.
Antibiotics 2013, 2(4), 500-534; https://doi.org/10.3390/antibiotics2040500
Submission received: 13 September 2013 / Revised: 28 November 2013 / Accepted: 29 November 2013 / Published: 6 December 2013
(This article belongs to the Special Issue Feature Paper 2013)
Versions Notes

Abstract

:
Many approaches are used to discover new antibiotic compounds, one of the most widespread being the chemical modification of known antibiotics. This type of discovery has been so important in the development of new antibiotics that most antibiotics used today belong to the same chemical classes as antibiotics discovered in the 1950s and 1960s. Even though the discovery of new classes of antibiotics is urgently needed, the chemical modification of antibiotics in known classes is still widely used to discover new antibiotics, resulting in a great number of compounds in the discovery and clinical pipeline that belong to existing classes. In this scenario, the present article presents an overview of the R&D pipeline of new antibiotics in known classes of antibiotics, from discovery to clinical trial, in order to map out the technological trends in this type of antibiotic R&D, aiming to identify the chemical classes attracting most interest, their spectrum of activity, and the new subclasses under development. The result of the study shows that the new antibiotics in the pipeline belong to the following chemical classes: quinolones, aminoglycosides, macrolides, oxazolidinones, tetracyclines, pleuromutilins, beta-lactams, lipoglycopeptides, polymyxins and cyclic lipopeptides.

1. Introduction

The continuous rise in the number of bacterial pathogens with resistance to the antibiotics on the market has prompted the urgent need for the development of new antibiotics. Currently there are three different approaches used in the discovery of new antibiotics: (1) development of new compounds that belong to new chemical classes and act on new targets; (2) development of new compounds that belong to new chemical classes and act on established targets; and (3) development of compounds belonging to existing classes that act on established targets [1].
However, the discovery of new chemical classes is a risky process [2]. Therefore, many companies developing new antibiotics are still pursuing the chemical modification of known antibiotics.
In this scenario, the present article presents an overview of the R&D pipeline of new antibiotics that belong to known classes of antibiotics, from discovery to clinical trials. With the information gathered, the article maps out the technological trends in this type of antibiotic R&D, identifying the chemical classes in which there is most R&D activity, the spectra of activity, the new subclasses, and the companies researching these types of compounds.
This article presents the different stages of R&D of companies developing new compounds in known chemical classes. Several articles [3,4,5,6,7,8,9] review the new antibiotic compounds in the clinical pipeline by analyzing their activity, technical and pharmacological properties. The contribution this article makes is to provide more wide-ranging information on the R&D pipeline at every phase of development, especially at pre-clinical and discovery stages, when there is little technical information available.
It is important to note that substances from the same chemical group have similar mechanisms of action and normally have the same basic structure, or scaffold, which is what lends the compounds their activity. The differences between the substances from the same group are caused by the peripheral chemical groups, which improve their pharmacological properties and can improve potency and antibacterial spectrum.

2. Experimental

The study consists of two stages, namely:
  • Identification of companies doing research and development into new antibiotics around the world;
  • Mapping of the antibiotic development pipelines of the companies identified.
The two stages will be developed using the following methodology:

2.1. Identification of Companies Doing R&D into New Antibiotics

The process of developing a new drug normally involves two major stages: the initial discovery stage and pre-clinical testing (in vitro and in vivo tests to determine efficacy, pharmacology, safety, etc.) and the clinical trial stage (involving trials on humans) [10,11].
Very little of the information produced at the discovery stage is published. When companies begin the clinical trials, they have to register the information in clinical trials register databases like clinicaltrials.gov, EU Clinical Trials Register (EU-CTR) and others, following the rules established by the World Health Organization [10,11].
As so little information is available on the discovery stage, this study identifies the companies working in the research and development of new antibiotics based on press releases and presentations by these companies in the business and health media. This information on the pharmaceuticals market is available on a global level and consolidated in the Chemical Business NewsBase (CBNB) database, which was chosen to be used in this study [12].
This database was mined for references with the words “antibacterial” or “antibiotic” in the R&D category published between 2006 and 2012. By analyzing these articles, companies working in the research and development of new antibiotics were identified.
The EvaluatePharma® database was used for each of the companies to see whether any of them had gone bankrupt, gone out of business or been acquired by other companies in the period under study.

2.2. Mapping the Companies’ New Antibiotics Pipeline

In this stage, the antibiotics developed by the companies and their stage of development (discovery phase, clinical trials, etc.) were identified. These data were collected from the companies’ own websites, from news published on the internet, articles retrieved from CBNB, scientific journals, patent applications and the clinical trial databases clinicaltrial.gov, ClinicalTrials.gov, a registry and results database of clinical studies of human participants conducted around the world, and International Clinical Trials Registry Platform (run by the WHO), that provides access to a central database containing the trial registration data sets provided by more than 15 registry databases. It also provides links to the full original records.

3. Pipeline of New Antibiotics in Chemical Classes Known on the Market

The chemical classes of antibiotics identified in the present study were: quinolones, aminoglycosides, macrolides, oxazolidinones, tetracyclines, pleuromutilins, beta-lactams, lipoglycopeptides, polymyxins, and cyclic lipopeptides. All the compounds, their phase of development, chemical class, and spectrum of activity are disclosed in Table 1.
Table
Table 1. Pipeline of antibiotics in known chemical classes.
Table 1. Pipeline of antibiotics in known chemical classes.
ClassCompound (Subclass)Company (Country)Development PhaseBacteriaChemical structureSource
Quinolones
NemonoxacinTaiGen Biotechnology (Taiwan)Phase IIIBroad-spectrum Antibiotics 02 00500 i001[13,14,15,16,17,18]
Ozenoxacin (topical use)Ferrer Internacional (Spain)Phase IIIGram-positive Antibiotics 02 00500 i002[19,20,21]
Zabofloxacin (fluoroquinolone)Dong Wha Pharmaceutical (South Korea)Phase IIIBroad-spectrum Antibiotics 02 00500 i003[22,23,24,25]
Delafloxacin (fluoroquinolone)Rib-X Pharmaceuticals (USA)Phase IIIBroad-spectrum Antibiotics 02 00500 i004[26,27,28]
Avarofloxacin (fluoroquinolone)Furiex Pharmaceuticals (USA)Phase II completedBroad-spectrum Antibiotics 02 00500 i005[29,30,31,32,33,34,35]
Finafloxacin (fluoroquinolone)MerLion Pharmaceuticals (Singapore)Phase IIH. pylori, Broad-Spectrum Antibiotics 02 00500 i006[36,37,38,39]
WCK 2349 a prodrug of WCK 771 a,b (fluoroquinolone)Wockhardt ( India)Phase IIGram-positive Antibiotics 02 00500 i007
S-(−)-nadifloxacin b		[40,41,42,43]
KRP-AM1977X (oral)Kyorin (Japan)Phase IRespiratory infections ND[44,45]
KRP-AM1977Y KyorinPhase IMRSAND[44,45]
DS-8587 (fluoroquinolone)Daiichi Sankyo (Japan)Phase IBroad-spectrum Antibiotics 02 00500 i008[46,47]
ACH-702 (Isothiazoloquinolone)Achillion Pharmaceuticals (USA)Pre-ClinicalBroad-spectrum Antibiotics 02 00500 i009[48,49]
Aminoglycosides
Plazomicin Achaogen (USA) Phase II completedBroad-spectrum Antibiotics 02 00500 i010[50,51,52,53,54,55,56]
Neomycin analogs cAchaogen (USA)DiscoveryBroad-spectrum Antibiotics 02 00500 i011[57,58,59,60,61,62,63]
FY-901Changzhou Fangyuan Pharmaceutical (China)Pre-ClinicalS. AureusND[64]
FY-902Changzhou Fangyuan PharmaceuticalPre-ClinicalM. tuberculosisND[64]
New compoundsChangzhou Fangyuan PharmaceuticalDiscoveryNDND[65]
Macrolides
Solithromycin (2-fluoroketolide)Cempra Pharmaceuticals (USA)Phase III S. pneumoniae; N. gonorrhoeae Antibiotics 02 00500 i012[66,67,68,69,70,71,72]
New Macrolides dCempra Pharmaceuticals DiscoveryND Antibiotics 02 00500 i013[73,74]
EDP-788 (bicyclolide-bridged bicyclic macrolide)Enanta Pharmaceuticals (USA)Pre-ClinicalGram-positiveND[75,76]
new bicyclolides cEnanta PharmaceuticalsDiscoveryGram-positive Antibiotics 02 00500 i014[77,78,79,80]
WCK 4873 (Ketolide)WockhardtPre-ClinicalMDR pneumoccocus, Strep, H. influenzaeND[81,82]
RX-02 program Rib-X Pharmaceuticals DiscoveryGram-positiveND[83]
Oxazolidinones
TedizolidCubist Pharmaceuticals (USA)Phase III Gram-positive Antibiotics 02 00500 i015[84,85,86,87,88]
CadazolidActelion (Switzerland)Phase II completedClostridium difficile Antibiotics 02 00500 i016[89,90,91,92]
Radezolid Rib-X PharmaceuticalsPhase II completedGram-positive Antibiotics 02 00500 i017[93,94,95,96,97,98]
AZD5847AstraZeneca (UK)Phase IIM. tuberculosis Antibiotics 02 00500 i018[99,100,101,102]
LCB01-0371LegoChem Biosciences (South Korea)Phase IGram-positive Antibiotics 02 00500 i019[103,104]
MRX-IMicuRx Pharmaceuticals (USA)Phase IGram-positive Antibiotics 02 00500 i020[105,106]
MRX-IIMicuRx PharmaceuticalsPre-ClinicalGram-positiveND[106]
2nd Generation OxazolidinonesWockhardtPre-ClinicalGram-positiveND[81]
Tetracyclines
Omadacycline (aminomethylcycline)Paratek (USA)Phase IIIBroad-spectrum Antibiotics 02 00500 i021[93,107,108]
AminomethylcyclinesParatekDiscoveryClostridium difficileND[107]
Eravacycline (fluorocycline)Tetraphase Pharmaceuticals (USA)Phase II (cIAI)Gram-negative Antibiotics 02 00500 i022[109,110,111,112]
TP-271Tetraphase PharmaceuticalsPre-Clinicalbacterial biothreats, CABP pathogens Antibiotics 02 00500 i023[109,113,114]
TP-834Tetraphase PharmaceuticalsPre-ClinicalCABP pathogensND[109]
New tetracycline derivatives cTetraphase PharmaceuticalsDiscoveryGram-negative Antibiotics 02 00500 i024[115,116,117,118]
Pleuromutilins
BC-3781 Nabriva (Austria)Phase II CompletedGram-positive, including MRSA Antibiotics 02 00500 i025[119,120,121,122,123,124]
BC-7013 (topical)Nabriva Phase IGram-positive Antibiotics 02 00500 i026[119,124]
Discovery/development of pleuromutilinsNabriva DiscoveryBroad spectrum Antibiotics 02 00500 i027[119,125,126,127]
Beta-lactams
Ceftolozane + tazobactam (CXA-201)Cubist PharmaceuticalsPhase IIIGram-negative Antibiotics 02 00500 i028
(ceftolozane)		[6,128,129,130,131,132]
BAL30072 (sulfactam)Basilea Pharmaceutica (Switzerland)Phase IGram-negative Antibiotics 02 00500 i029[133,134,135]
S-649266 (GSK2696266) (Cephalosporin)Shionogi (Japan)/ GlaxoSmithKline (UK)Phase IGram-negativeND[136,137,138]
CB-027 (Cephalosporin)Cubist PharmaceuticalsPre-ClinicalBroad-spectrumND[139]
FSI-1671 (Carbapenem)FOB Synthesis, Inc. (USA)Pre-ClinicalGram-negative Antibiotics 02 00500 i030[140,141]
Beta-lactamase inhibitors—Diazabicyclooctanes (DBOs)
Ceftazidime/Avibactam (CAZ AVI) e Forest Laboratories (USA)/AstrazenecaPhase IIIGram-negative Antibiotics 02 00500 i031
(avibactam)		[142,143,144,145,146,147,148]
Ceftaroline/Avibactam (CXL) eForest Laboratories/ AstrazenecaPhase IIGram-negative Antibiotics 02 00500 i032
(avibactam)		[120,143,147,148,149,150,151]
MK-7655 + Imipenem/Cilastatin Merck & Co., Inc. (USA) Phase IIGram-negative Antibiotics 02 00500 i033
(MK-7655)		[6,147,148,152,153,154,155]
FPI-1465Fedora Pharmaceuticals Inc. (USA)Pre-ClinicalGram-negative Antibiotics 02 00500 i034[156,157]
Beta-lactamase inhibitors—Boronate β-lactamase inhibitor
Carbavance (biapenem + RPX7009) Rempex Pharmaceuticals (Sweden)Phase IGram-negative Antibiotics 02 00500 i035
(RPX7009)		[158,159,160,161]
Beta-lactamase inhibitors—phosphonate-based beta-lactamase inhibitor (BLI)
MG96077Mirati Therapeutics (USA)Pre-ClinicalGram-negative Antibiotics 02 00500 i036[162,163]
Lipoglycopeptides
Dalbavancin Durata Therapeutics (USA)Phase III completedGram-positive Antibiotics 02 00500 i037[164,165,166,167,168,169,170,171,172,173]
Oritavancin DiphosphateThe Medicines Company (USA)Phase III completedGram-positive Antibiotics 02 00500 i038[7,169,170,173,174]
Polymyxins
NAB739Northern Antibiotics (Finland)Pre-ClinicalGram-negative Antibiotics 02 00500 i039[89,175,176,177,178,179]
NAB7061Northern AntibioticsPre-ClinicalGram-negative Antibiotics 02 00500 i040[176,177,178,179]
NAB741Northern AntibioticsPre-ClinicalGram-negative Antibiotics 02 00500 i041[176,177,178,179]
Cyclic lipopeptides
Surotomycin Cubist PharmaceuticalsPhase IIIC. difficile Antibiotics 02 00500 i042[180,181,182,183]
WAP-8294A2 (lotilibcin)Green Cross (South Korea)Phase IS. aureusND[184,185,186]
ND: Not Divulged; a The company has not yet published the chemical structure of WCK 2349; b WCK 771 is the arginine salt of S-(−)-nadifloxacin; c Please find the substituents in the specific claimed compounds on the referenced patents; d The compound described is the only specific claimed compound in the referenced patent; e Ceftaroline and ceftazidimeare new cephalosporins already marketed in some countries.
Below, we set forth information about each compound identified and its stage of development.

4. Quinolones

There are eleven new quinolones under clinical development and one in the pre-clinical phase of development. The companies pursuing new quinolones are: TaiGen Biotechnology, Kyorin, Ferrer Internacional, Dong Wha Pharmaceutical, Rib-X Pharmaceuticals, Furiex Pharmaceuticals, MerLion Pharmaceuticals, Wockhardt, Daiichi Sankyo, and Achillion Pharmaceuticals. Most of the compounds are fluoroquinolones, but there is one new class of quinolone: isothiazoloquinolones (ITQs).
Nemonoxacin, developed by TaiGen Biotechnology, is a novel nonfluorinated broad-spectrum quinolone. The compound shows greater in vitro activity (compared to ciprofloxacin, levofloxacin and moxifloxacin) against Gram-positive bacteria, including resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant (MDR) Streptococcus pneumonia. The activity against most Gram-negative bacteria is similar to that of levofloxacin and moxifloxacin [13].
The company has finished one Phase III clinical study comparing the new compound to levofloxacin for the treatment of community-acquired pneumonia and has submitted a new drug application for the oral formulation of the drug in Taiwan (Taiwan Food and Drug Administration) and China (China Food and Drug Administration) [13,15,17,18]. The compound is also under development for the treatment of diabetic foot infection, for which the company has finished one Phase II clinical trial [16].
Ferrer Internacional has completed one Phase III clinical trial to evaluate the topical formulation of ozenoxacin in the treatment of impetigo [21].
Zabofloxacin is a broad-spectrum antibiotic. The compound shows enhanced activity against both quinolone-susceptible and -resistant Streptococcus pneumonia [22,23]. The compound is under development for treatment of chronic obstructive pulmonary disease (COPD) with acute exacerbation. The company is currently recruiting patients for the Phase III clinical trial of oral zabofloxacin compared to moxifloxacin [24,25].
Delafloxacin, developed by Rib-X Pharmaceuticals, is a broad-spectrum fluoroquinolone with improved activity against Gram-positive bacteria when compared to other marketed quinolones. The antibacterial potency of delafloxacin decreases when the pH is slightly reduced, unlike other quinolones such as ciprofloxacin and moxifloxacin, which minimum inhibitory concentration (MIC)’s value increases as the pH decreases. This feature enhances the antibacterial potency in environments with reduced pH such as infection sites that contain inflammatory cells. The compound is active against quinolone susceptible and resistant MRSA strains. The activity against Gram-negative bacteria has shown to be similar to that of ciprofloxacin [26].
The company is currently recruiting patients for a Phase III clinical trial to evaluate delafloxacin compared with vancomycin and aztreonam for the treatment of patients with acute bacterial skin and skin structure infections [26,27,28].
There are three new fluoroquinolones in Phase II of clinical development: avarofloxacin, from Furiex Pharmaceuticals, finafloxacin, from MerLion Pharmaceuticals; and WCK 2349, from Wockhardt.
Avarofloxacin is a novel broad-spectrum fluorinated 4-quinolone. When compared to other marketed fluoroquinolones, the compound shows increased in vitro activity against Gram-positive bacteria, including fluoroquinolone-resistant MRSA. The activity of avarofloxacin was equivalent to that of moxifloxacin against Gram-negative bacteria [33,34,35].
In December of 2011, Furiex Pharmaceuticals completed a Phase II study to evaluate avarofloxacin for treating complicated skin and skin structure infections compared to linezolid. The compound is Phase III ready and has received Qualified Infectious Disease Product and Fast Track designations from the US Food and Drug Administration. The company is seeking partners to continue the development of avarofloxacin [29,30,31,32,33,34].
Finafloxacin is a novel fluoroquinolone being developed by MerLion Pharmaceuticals. Under neutral pH conditions (pH 7.2–7.4), the compound has shown in vitro activity equivalent to that of ciprofloxacin. However, under slightly acidic pH5.8 the compound shows enhanced potency. Other marketed fluoroquinolones, such as ciprofloxacin, levofloxacin and moxifloxacin, exhibit reduced activity at slightly acidic pH 5.0–6.5. This feature of finafloxacin makes the compound suitable for use in the treatment of infections in acidic foci of infections such as urinary tract infections [39,187,188].
MerLion Pharmaceuticals has announced that the FDA has granted a Qualified Infectious Disease Product Designation and Fast Track Status for finafloxacin. The company is currently recruiting patients for the Phase II clinical trial of the compound for the treatment of complicated urinary tract infections (cUTI) and/or acute pyelonephritis compared to ciprofloxacin [37,38].
WCK 2349 is a prodrug of WCK 771, which is the hydrate of the arginine salt of S-(‒)-nadifloxacin. WCK 771 is a broad-spectrum fluoroquinolone with improved antibacterial activity against quinolone-resistant staphylococci, particularly quinolone resistant MRSA strains [189,190].
In June of 2013 Wockhardt completed a Phase II clinical trial in India of WCK 2349 on the treatment of complicated skin and soft tissue infections [40,41,42]. Results have not been published yet.
The other non-fluorinated quinolone under clinical development is KRP-AM1977, by Kyorin, which is in Phase I of clinical trials. The oral formulation of the compound (KRP-AM1977X) is being tested for treatment of respiratory infections and the I.V. formulation is under development for treatment of MRSA infections [44,45].
DS-8587, from Daiichi Sankyo, is a fluoroquinolone with improved activity against both Gram-negative and Gram-positive bacteria. The compound is especially effective against Acinetobacter baumannii [46,47] but also has improved activity against streptococci, staphylococci, enterococci, E. coli, and anaerobes [191]. The compound is currently under Phase I of clinical development [47].
Achillion Pharmaceuticals is working on the discovery of compounds in a new subclass of quinolones, the isothiazoloquinolones. The most advanced compound is ACH-702, which is at the pre-clinical stage of development [48,192].
When compared to levofloxacin, oxacillin and linezolid, the compound shows enhanced in vitro activity against Gram-positive bacteria, including fluoroquinolone resistant MRSA. Regarding Gram-negative bacteria, ACH-702 showed improved in vitro activity against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria sp. and anaerobes. However, it showed less activity against Enterobacteriaceae when compared to ciprofloxacin, moxifloxacin, ceftazidime, imipenem and gentamicin [49].
The company is also working on the development of ACH-702 analogs with efficacy against M. tuberculosis [48,49].

5. Aminoglycosides

There are two companies working on the discovery and development of aminoglycosides: Achaogen and Changzhou Fangyuan Pharmaceutical
Achaogen is pursuing the discovery of new compounds through the optimization of leading compounds from their portfolio of aminoglycosides. The company has published six patent applications for new aminoglycoside compounds in the last two years [53,57].
Also, the company is developing the only aminoglycoside in the clinical stage of development, plazomicin. This compound belongs to a new subclass of aminoglycosides: neoglycosides. It is active against Gram-negative and Gram-positive bacteria and has significantly improved activity against strains resistant to amikacin and/or gentamicin. The compound also shows enhanced activity against resistant Enterobacteriaceae, Acinetobacter, Pseudomonas, and Staphylococcus, including Klebsiella pneumoniae carbapenemase (KPC), extended-spectrum beta-lactamase (ESBL) and metallo-beta-lactamase producing Enterobacteriaceae and MRSA [51,93,193,194].
A multi-national Phase II study of plazomicin in comparison to levofloxacin for the treatment of complicated urinary tract infections and acute pyelonephritis in adults has been completed. The company announced that that the study met its objectives and the results would be published in an upcoming medical conference [55].
To continue the development of plazomicin, the company has received a contract option of US$ 60M from the Biomedical Advanced Research and Development Authority (BARDA) to support a global Phase III clinical study. The study will evaluate plazomicin in treating patients with serious Gram-negative bacterial infections due to carbapenem-resistant Enterobacteriaceae. The study is expected to start in the fourth quarter of 2013 [54].
Changzhou Fangyuan Pharmaceutical is working on the discovery of new aminoglycosides and currently has two compounds in the pre-clinical testing phase: FY-01 to treat S. aureus infections, and FY-02 for tuberculosis. The company has published six patent applications for new aminoglycoside compounds in the last two years [57,65].

6. Macrolides

Five companies are pursuing the development of new macrolides: Cempra Pharmaceuticals, Enanta Pharmaceuticals, Wockhardt, Basilea Pharmaceutica, and Rib-X Pharmaceuticals.
Cempra Pharmaceuticals is researching new macrolide antibiotics in a library licensed from Optimer. In the last two years the company has published one patent application for new macrolide compounds. The company is developing solithromycin, the first antibiotic from the 2-fluoroketolide subclass. It is the new compound in the most advanced development phase.
Solithromycin shows improved binding to the ribosomal target and has broad-spectrum activity against macrolide and ketolide-resistant bacteria. The compound is active against the major community-acquired bacterial pathogens, including multi-drug-resistant community-acquired pneumococci, Haemophilus influenzae, Moraxella catarrhalis, and methicillin-susceptible Staphylococcus aureus (MSSA) [93]. The compound is active against most off the MRSA strains isolated from community-acquired bacterial pneumonia (CABP), however, MRSA strains with constitutive macrolide resistance are resistant to solithromycin [72].
Macrolides are used in combinations with beta-lactams for the treatment of CABP due to the increasing macrolide resistance in M. pneumonia. For the same reason the use of respiratory fluoroquinolones in CABP has increased as a choice of monotherapy [72]. Since it is not possible to treat CAPB with telithromycin not associated with a beta-lactam, the compound is being developed in comparison to moxifloxacin.
The company is recruiting patients for a Phase III clinical study of the oral formulation of solithromycin comparing its activity to that of moxifloxacin for the treatment of patients with community-acquired bacterial pneumonia. It also has one completed Phase II clinical study for the treatment of uncomplicated urogenital gonorrhea with positive outcomes [66,67].
Enanta Pharmaceuticals is working on the discovery and development of bicyclolides (bridged bicyclic macrolides) a new subclass of macrolide antibiotics. The company has published two patent applications for new bicyclolides compounds in the last two years [79,80]. The most advanced compound is EDP-788 (a prodrug of EDP-322) that demonstrates a broad spectrum of activity against many bacterial organisms, including MRSA [75].
The compound is currently in pre-clinical development for intravenous and oral formulations, with ongoing investigational new drug (IND) enabling studies. The study is funded under the company’s contract with the National Institute of Allergy and Infectious Diseases (NIAID), with potential for further NIAID funding of early clinical development. The Phase I clinical trials are supposed to begin in 2014 [75,77,78].
Wockhardt is developing a new second-generation ketolide compound, WCK 4873, which is in early pre-clinical development for the oral treatment of infections caused by multi-drug-resistant streptococci, pneumococci and H. influenzae. The company has completed regulatory toxicology studies for the compound and is currently in the formulation development phase [81,82].
Basilea Pharmaceutica is pursuing new macrolides using the experience acquired during the identification and characterization of BAL19403, a macrolide compound active against P. acnes, with the last stage of development having been reported in 2007 [195].
The RX-02 discovery program at Rib-X Pharmaceuticals is focused on finding new macrolides designed to overcome known ribosomal resistance modifications in a wide range of pathogens. The company is currently seeking partners for the development of this program [83].

7. Oxazolidinones

The oxazolidinones are a new class of antibiotics with strong activity against nearly all Gram-positive organisms, including those resistant to other agents. Linezolid was the first member of this class introduced to the market. Although it is an effective antibiotic, new compounds in this class are needed against linezolid-resistant strains and to overcome the side effects caused by the compound.
Seven companies are developing new oxazolidinones: Cubist Pharmaceuticals, Actelion, Rib-X Pharmaceuticals, AstraZeneca, LegoChem Biosciences, MicuRx Pharmaceuticals, Wockhardt.
Cubist Pharmaceuticals is developing tedizolid phosphate (TR-701), a pro-drug of TR-700, which exhibits improved activity against all clinically relevant Gram-positive bacteria, including linezolid resistant S. aureus [86].
The compound is in a late stage of development, with two completed Phase III clinical studies to evaluate tedizolid compared to linezolid for the treatment of acute bacterial skin and skin structure infections, both trials showing positive results. The company announced that it had submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of the new drug for treatment of acute bacterial skin and skin structure infections (aBSSSi). The company plans to initiate a Phase III study of tedizolid in patients with severe pneumonia during the second half of 2013 [88,196,197,198].
Cadazolid is a new oxazolidinone with a fluoroquinolone side chain (hybrid antibiotic) [89,91]. The compound has shown to have potent activity against Clostridium difficile bacteria and is being developed by Actelion for treatment of Clostridium difficile-associated diarrhea (CDAD). The company completed a Phase II clinical study in 2012 to an oral formulation of Cadazolid for treatment of CDAD and is planning to start a Phase III study in the fourth quarter of 2013 [90,92].
Rib-X Pharmaceuticals has completed two Phase II clinical trials of radezolid for the treatment of pneumonia and uncomplicated skin infections. The trial completion dates were in 2008 and 2009, but to date the Phase III trials have not been initiated [93,94,95,96,97].
AstraZeneca is currently pursuing the development of AZD5847, a new oxazolidinone active against Gram-positive bacteria and mycobacteria. AZD5847 is active against a broad array of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. The compound is under Phase IIa clinical development to assess early bacterial activity of the compound. The company is currently recruiting participants to be part of the trial [99,100,101].
LCB01-0371 is being developed by LegoChem Bio. This new oxazolidinone has improved activity against Gram-positive pathogens and has good pharmacokinetic profiles in animals [103].
The compound is under Phase I clinical development to assess the safety and tolerability of the compound. The company is currently recruiting participants to be part of the trial [103,104].
MicuRx Pharmaceuticals is developing two oxazolidinone compounds MRX-I and MRX-II. MRX-I is an oral oxazolidinone antibiotic that targets infections due to resistant Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE). The company announced the completion of a double-blinded, placebo-controlled Phase 1 clinical study, and that the compound has been shown to be safe and well-tolerated at all doses tested with no evidence of myelosuppression. In October 2012, the company announced the establishment of Shanghai MengKe Pharmaceuticals, a joint venture with Shanghai Zhangjiang Biomedical Industry Venture Capital formed to fund the development and commercialization of MRX-I for the Chinese market. MRX-II is currently under pre-clinical development [105,106].
Wockhardt is also working on the development of second-generation oxazolidinones, which are in pre-clinical testing for Gram-positive infections [81].

8. Tetracyclines

Two companies were found to have tetracycline antibiotic R&D: Paratek and Tetraphase.
Paratek is developing a new subclass of tetracyclines called aminomethylcyclines. Omadacycline, the lead compound, is a broad-spectrum antibiotic with improved activity against tetracycline-resistant pathogens, including methicillin-susceptible and -resistant staphylococci as well as streptococci and enterococci. The compound is also active against many clinically important Enterobacteriaceae and a wide range of anaerobes [199].
The compound is currently under development for the treatment of ABSSI, CABP and UTI. The company had started a Phase III trial for complicated skin and skin structure infections (cSSSI) in March 2010, when the FDA notified that it would modify the guidance on the conduct of studies for this indication. With these modifications, the Phase III trial design did not align with the FDA’s then-evolving guidance for trials aimed at supporting the approval of an antibiotic for the treatment of aBSSSI. As a result, the Phase III trial was terminated after having enrolled 140 of the planned 790 subjects.
The FDA has since granted Omadacycline Qualified Infectious Disease Product (QIDP) designation for oral and IV formulations in the treatment of aBSSSi and CABP. The Phase III studies will be conducted under two special protocol assessment agreements, one for aBSSSI and one for CABP. Paratek is currently planning additional studies of omadacycline for the treatment of urinary tract infection. The company plans to simultaneously conduct two Phase III registration trials for aBSSSI, and submit an NDA for the treatment of aBSSSI in late 2014 [200].
Tetraphase Pharmaceuticals is developing a new class of synthetic tetracyclines, called fluorocyclines. The company has published three patent applications for new tetracycline compounds in the last two years [116,117,118]. The lead compound is eravacycline, a broad-spectrum fluorocycline antibiotic with activity against bacteria expressing major antibiotic resistance mechanisms, including tetracycline-specific efflux and ribosomal protection. The compound has improved activity against many MDR Gram-negative bacteria, including beta-lactam resistant E. coli, K. pneumoniae and Acinetobacter spp.
The company successfully completed a Phase II clinical study in 2012 to evaluate the safety of the intravenous formulation of eravacycline for the treatment of cIAI, and started a Phase III study in August of 2013 [201]. They announced that they expect to begin the cUTI Phase III clinical trial in the fourth quarter of 2013 [202].
The company has two other fluorocyclines in the pipeline, both in pre-clinical testing: TP-271, for the treatment of bacterial biothreats and CABP pathogens, and TP-834, active against CABP pathogens. The company is also working to discover novel tetracycline derivatives or treatment of Gram-negative infections [109,113,114].

9. Pleuromutilins

Pleuromutilins have been known since 1951, but only entered the market in 2007 with the approval of retapamulin for topical use. Until today, there are no pleuromutilins for systemic use approved in human clinical practice.
Nabriva is currently working on the development of new compounds is this class. The lead compound, BC-3781, if approved, will be the first pleuromutilin for systemic use in humans.
The compound shows potent in vitro activity against a large collection of staphylococci, streptococci, and E. faecium. When compared to linezolid and vancomycin, the compound shows greater overall potency against S. aureus [121]. BC-3781 shows improved activity against most bacteria commonly associated with community-acquired respiratory tract infections, the compound is especially potent against S. pneumonia including penicillin resistant strains. It also shows improved activity against H. influenza, M. catarrhalis, M. pneumoniae and C. pneumoniae.
BC-3781 is undergoing Phase I clinical trials for CAP and in March of 2011 has completed a Phase II clinical study comparing it to vancomycin for treatment of aBSSSI [119,120,121,122,123]. Nabriva Therapeutics AG announced that the cooperation with Forest Laboratories to develop the compound had elapsed, and that Nabriva retained all rights in BC-3781. The company informed that the product was Phase III ready and that it was seeking partners to continue further development [203].
Nabriva is also developing BC-7013 for topical use against Gram-positive infections and working on the discovery of new pleuromutilins [119,124].

10. Beta-Lactams

BAL30072 is a novel monosulfactam under clinical development. The compound has shown improved in vitro activity against significant Gram-negative pathogens especially against A. baumannii where it has shown to be active against meropenem-resistant strains. The compound also presents improved activity against P. aeruginosa, Burkholderia cepacia, and some MDR Enterobacteriaceae, however, it shows lower potency against ESBL-producing Enterobacteriaceae [4,204].
Basilea Pharmaceutica is conducting Phase I studies to assess the pharmacokinetics, safety and tolerability of BAL30072. The company announced that it had received a contract of USD17 million with BARDA, to continue the Phase 1 studies of safety and tolerability of BAL30072 alone and in combination with carbapenems [133,134,135].
There are four cephalosporins under development. The cephalosporin in the most advanced phase of development is ceftolozane a novel oxyimino-aminothiazolyl cephalosporin, which is under development in combination with tazobactam to treat infections by Gram-negative pathogens.
The ceftolozane/tazobactam combination has demonstrated improved in vitro activity against P. aeruginosa (including to MDR strains) when compared to ceftazidime and cefepime. The combination is also more active than ceftazidime and piperacillin-tazobactan against ceftazidime-resistant Enterobacteriaceae species. However, ceftolozane/tazobactam is less active than cefepime against some species of ceftazidime-resistant Enterobacteriaceae [205].
The company is recruiting patients for four ongoing Phase III clinical trials: two comparing the ceftolozan/tazobactam combination with levofloxacin for treatment of cUTI and another two comparing the combination with meropenem for treatment of cIAI [6,128,129,130,131].
GlaxoSmithKline is developing S-649266 (GSK2696266) with Shionogi. The compound is active against Gram-negative bacteria and is has strong anti-bacterial activity against New Delhi metallo-beta-lactamase-1 (NDM-1) producing bacteria, which have developed resistance to many carbapenem and cephem antibiotics [137]. S-649266 is currently in Phase I of clinical trials [136,137,138].
The cephalosporin under pre-clinical development is CB-027, being developed by Cubist Pharmaceutical, which has shown potent in vitro activity against both Gram-positive and Gram-negative bacteria including MRSA and Pseudomonas aeruginosa. The in vivo activity against clinical isolates of MRSA was shown to be comparable to vancomycin and ceftaroline. CB-027 also had good activities against ceftazidime-resistant Pseudomonas aeruginosa and Klebsiella pneumonia [139,206].
FOB Synthesis, Inc. is developing FSI-1671, a novel carbapenem. The compound shows improved in vitro activity against A. baumannii, including to MDR-strains, and the FSI-1671/sulbactam combination showed synergy against MDR-A. baumannii [140,141]. FOB synthesis presented the results of the pre-clinical studies in the 53rd International Interscience Conference on Antimicrobial Agents and Chemotherapy, but has not informed if will pursue further development of the compound.

11. Beta-Lactamase Inhibitors—Diazabicyclooctanes (DBOs)

Diazabicyclooctanes (DBOs) are a rich source of β-lactamase inhibitors (BLI). Two members of this novel series are now in clinical development, avibactam and MK-7655. Both compounds are broad-spectrum beta-lactamase inhibitors and are more potent compared to tazobactam [147,148].
Avibactam is being developed by Forest Laboratories and Astrazeneca in combination with ceftazidime and ceftaroline for the treatment of Gram-negative infections. The compound demonstrated in vitro activity against Ambler class A and C β-lactamases, including KPC, and some class D enzymes [207].
The use of avibactam with ceftazidime improves the activity of the compound against most species of beta-lactamase producing Enterobacteriaceae and against Pseudomonas aeruginosa [208].
This feature makes the combination ceftazidime/avibactam suitable for treatment of infections with resistant Gram-negative bacilli-producing ESBL, KPC and/or AmpC beta-lactamases and for treatment of P. aeruginosa infections [208].
Five Phase III clinical trials are currently recruiting patients to evaluate the use of ceftazidime/ avibactam for the treatment of complicated urinary tract infection, complicated intra-abdominal infection, nosocomial pneumonia and ventilator-associated pneumonia [142,143,144,145,146,147,148].
The combination ceftaroline/avibactam has shown activity equivalent to that of ceftazidime/avibactam with two exceptions, the activity against MRSA and limited activity against P. aeruginosa [209].
In July 2012, the companies completed the Phase II clinical study of intravenous ceftaroline fosamil/avibactam compared to intravenous doripenem in adults with complicated urinary tract infection. Phase III has not yet started [120,143,149,150,151].
Merck & Co., Inc. is currently developing MK-7655, to be used in combination with imipenem/ cilastatin. MK-7655 demonstrated potent in vitro inhibition of class A and class C β-lactamases [155].
The compound improves the activity of imipenem against Enterobacteriaceae producing KPC carbapenemases or combinations of β-lactamase and impermeability. It does not improve the activity of imipenem against metallo-carbapenemases producing Enterobacteriaceae. The activity of imipenem against P. aeruginosa generaly improved, particularly OprD mutants [210].
There are two Phase II clinical studies currently recruiting patients to evaluate the combination of MK-7655 + imipenem/cilastatin compared to imipenem/cilastatin alone in the treatment of cUTI and cIAI [152,153,154,155].
Fedora Pharmaceuticals Inc. is developing FPI-1465, which is currently under pre-clinical testing. Preliminary in vitro tests have shown that the compound inhibits ESBL enzymes of several Enterobacteriaceae species such as CTX-M and plasmid AmpC. The compound has demonstrated synergistic effects with aztreonam and ceftazidime [156,211]. The company has announced that it expects to file an Investigational New Drug (IND) application and initiate clinical studies in 2014 [157].

12. Beta-Lactamase Inhibitors—Boronate β-Lactamase Inhibitor

Rempex Pharmaceuticals is developing carbavance, a combination of biapenem and a new beta-lactamase inhibitor, RPX7009, for the treatment of Gram-negative infections. The combination is in Phase I of clinical trials [158,159,160].

13. Beta-Lactamase Inhibitors—Non-beta-Lactam Phosphonate-Based

Mirati Therapeutics is seeking partners to continue the development of the compound MG96077, a non-beta-lactam phosphonate-based beta-lactamase inhibitor that has shown an inhibitory profile for both class A and class C beta-lactamase enzymes [162,163].

14. Glycopeptides (Lipoglycopeptides)

Telavancin is the first approved compound of the lipoglycopeptides, a new class of antibiotics. Two other lipoglycopeptides are in Phase III of clinical development: dalbavancin, by Durata Therapeutics, and oritavancin diphosphate, by The Medicines Company. Both are in development for the treatment of aBSSSi.
All three compounds demonstrate bactericidal activity against MSSA, MRSA, methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistent Staphylococcus epidermidis (MRSE) and penicillin-resistant S. pneumonia, therefore may be used for the treatment of resistant Gram-positive pathogens replacing vancomycin in cases of resistance or intolerace of vancomycin adverse effects [212].
Durata Therapeutics has completed two global Phase III clinical trials of dalbavancin for the treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria, and is preparing a new drug application to the FDA [164,168].
The Medicines Company completed the second Phase III clinical trial of oritavancin diphosphate for the treatment of aBSSSi in December 2012 [164,165,166,167,168,169,170,171,172,173]. The company announced that it plans to submit a New Drug Application to the FDA in the fourth quarter of 2013 [170,171,213].

15. Polymyxins

Polymyxins act by interacting with the phospholipids of the cell membrane and disrupting it, causing permeability leading to bacterial death. These compounds are active only against Gram-negative bacteria. Their systemic use is not recommended because of toxicity reasons, but there has been a resurgence in the systemic use of polymyxins due to the emergence of multidrug-resistant Gram-negative organisms [214].
The only company identified that has polymyxins in the pipeline is Northern Antibiotics, which is conducting pre-clinical testing of three polymyxin compounds. NAB739 has shown improved antibacterial activity against Gram-negative pathogens. The other two compounds, NAB7061 and NAB741, lack direct activity but improve the activity of other antibiotics against these bacteria when used together [175,176,177].
NAB739 has demonstrated activity similar to that of polymyxin B against a set of clinical isolates of E. coli. However it has shown an overall narrower antibacterial in vitro profile than polymyxin B, because of the decreased activity against Acinetobacter spp. and weaker activity against P. aeruginosa. The clinical importance of the NAB739 compound will be determined by studies comparing the nephrotoxicity of NAB739 and polymyxin B in vivo and the in vivo activity of the compound against Gram-negative bacteria [175].

16. Cyclic Lipopeptides

Cyclic lipopeptides, with activity against Gram-positive bacteria, are a new class of antibiotics in clinical practice, and daptomycin is the first and only antibiotic in this class. This compound works by binding to bacterial membranes, which results in depolarization, loss of membrane potential, and cell death [214].
Two cyclic lipopeptides were identified in the clinical pipeline: surotomycin, from Cubist Pharmaceuticals, and WAP-8294A2 (lotilibcin), from Green Cross.
Surotomycin, developed by Cubist Pharmaceuticals, is structurally related to daptomycin and shares the mechanism of action against Clostridium difficile [183].
The company is currently recruiting patients for a Phase III clinical study comparing the new compound to vancomycin in the treatment of CDAD [180,181,182,183].
Green Cross is conducting a Phase I clinical trial to assess the safety of the new compound WAP-8294A2 (lotilibcin), under development for the treatment of infections caused by S. aureus [184,185,186].

17. Final Remarks

This article maps out the R&D of new antibiotics from known chemical classes, from the discovery stage to clinical trials. Many compounds were identified at the pre-clinical and development stages, but there is very little information divulged at such early stages of development.
Concerning the compounds under clinical testing, of the ten antibiotic classes identified, seven had compounds at Phase III, namely: quinolones (nemonoxacin for CAP; delafloxacin for aBSSSi), macrolides (solithromycin for CAP), oxazolidinones (tedizolid for aBSSSi; omadacycline for CAP, aBSSSi and UTI), cephalosporins (ceftolozane + tazobactam for cUTI and cIAI), lipoglycopeptides (dalbavancin for aBSSSi; oritavancin diphosphate for aBSSSi) and cyclic lipopeptides (surotomycin for CDAD).
Quinolones are the leading antibiotic class, with nine compounds under clinical testing by six companies from different parts of the world (Taiwan, Japan, South Korea, USA, India). Oxazolidinones are also an important class, with three compounds in clinical trials and five companies working in R&D.
Interestingly, of the chemical classes identified, only oxazolidinones, lipoglycopeptides and cyclic lipopeptides are recent classes (new compounds since 2000); the others are classes discovered prior to the 1970s.
Concerning the activity of the compounds, it can be seen that the recent trend in new antibiotic development has been on the development of new compounds in known chemical classes for the treatment of Gram-positive bacterial infections, which is reflected in the great number of compounds for aBSSSI and CABP undergoing clinical trials.
Among the compounds in clinical testing, only a few showed enhanced activity against MDR-Gram-negative bacteria. Plazomicin and eravacycline have shown a broad-spectrum activity against most MDR-Gram-negative bacteria. However, most of the development against Gram-negative bacteria is relying on the development of new and more potent beta-lactamase inhibitors to partly restore the activity of known antibiotics. It is uncertain if this approach will be effective to overcome serious MDR-Gram-negative infections. If this approach fails, there are only a few other new compounds from known classes under development to treat these types of infection.
The eight compounds in Phase III mapped out in the present article show that it is likely that in the near future the new chemical compounds from known classes will be very important for treating infections by increasingly resistant bacteria.
It is concluded that many companies are still keen to develop new antibiotics by modifying compounds from existing chemical classes. The number of companies pursuing such an approach in their R&D at different stages indicates that this kind of research is very important and will be a reality for a good while yet.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fischbach, M.; Walsh, C. Antibiotics for emerging pathogens. Science 2009, 325, 1089–1093. [Google Scholar] [CrossRef]
  2. Walsh, C.; Wencewicz, T. Prospects for new antibiotics: A molecule-centered perspective. J. Antibiot. 2013. [Google Scholar] [CrossRef]
  3. Ziemska, J.; Rajnisz, A.; Solecka, J. New perspectives on antibacterial drug research. Cent. Eur. J. Biol. 2013, 8, 943–957. [Google Scholar] [CrossRef]
  4. Boucher, H.W.; Talbot, G.H.; Benjamin, D.K.; Bradley, J.; Guidos, R.J.; Jones, R.N.; Murray, B.E.; Bonomo, R.A.; Gilbert, D. 10 × '20 Progress—Development of new drugs active against Gram-negative bacilli: An update from the infectious diseases society of America. Clin. Infect. Dis. 2013, 56, 1685–1694. [Google Scholar]
  5. Bassetti, M.; Merelli, M.; Temperoni, C.; Astilean, A. New antibiotics for bad bugs: Where are we? Ann. Clin. Microbiol. Antimicrob. 2013, 12. [Google Scholar] [CrossRef]
  6. Karras, G.; Giannakaki, V.; Kotsis, V.; Miyakis, S. Novel antimicrobial agents against multi-drug-resistant Gram-negative bacteria: An overview. Recent Pat. Antiinfect. Drug Discov. 2012, 7, 175–181. [Google Scholar] [CrossRef]
  7. Giannakaki, V.; Miyakis, S. Novel antimicrobial agents against multi-drug-resistant Gram-positive bacteria: An overview. Recent Pat. Antiinfect. Drug Discov. 2012, 7, 182–188. [Google Scholar] [CrossRef]
  8. Bush, K. Improving known classes of antibiotics: An optimistic approach for the future. Curr. Opin. Pharmacol. 2012, 12, 527–534. [Google Scholar] [CrossRef]
  9. Butler, M.S.; Blaskovich, M.A.; Cooper, M.A. Antibiotics in the clinical pipeline in 2013. J. Antibiot. 2013. [Google Scholar] [CrossRef]
  10. Collier, J.; Iheanacho, I. The pharmaceutical industry as an informant. Lancet 2002, 360, 1405–1409. [Google Scholar] [CrossRef]
  11. World Health Organization. WHO International Clinical Trials Registry Platform (ICTRP). Available online: http://www.who.int/ictrp/en/ (accessed on 30 December 2012).
  12. Dialog LLC. Chemical Business NewsBase (CBNB)—Bluesheet. Available online: http://library.dialog.com/bluesheets/html/bl0319.html (accessed on 17 February 2013).
  13. Beining, G.; Xiaojie, W.; Yingyuan, Z.; Yaoguo, S.; Jicheng, Y.; Guoying, C.; Jing, Z. Safety and clinical pharmacokinetics of nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and multiple oral doses. Clin. Drug Investig. 2012, 32, 475–486. [Google Scholar] [CrossRef]
  14. Chung, D.T.; Tsai, C.-Y.; Chen, S.-J.; Chang, L.-W.; King, C.-H.R.; Hsu, C.-H.; Chiu, K.-M.; Tan, H.-C.; Chang, Y.-T.; Hsu, M.-C. Multiple-dose safety, tolerability, and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers. Antimicrob. Agents Chemother. 2010, 54, 411–417. [Google Scholar] [CrossRef]
  15. TaiGen Biotechnology. Study to evaluate the efficacy and safety of oral administration with nemonoxacin and levofloxacin in patients with CAP. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01529476 (accessed on 15 April 2013).
  16. TaiGen Biotechnology. Safety and efficacy study of TG-873870 (Nemonoxacin) in diabetic foot infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00685698 (accessed on 15 July 2013).
  17. TaiGen Biotechnology. Nemonoxacin: Once-a-day oral and IV, with excellent activity toward MRSA and VRSA. Available online: http://www.taigenbiotech.com.tw/research.html (accessed on 15 April 2013).
  18. TaiGen Biotechnology. TaiGen Biotechnology announces submission of new drug application for nemonoxacin in Taiwan and China. Available online: http://www.taigenbiotech.com.tw/news.html#25 (accessed on 15 July 2013).
  19. Ferrer Group. Key development projects. Available online: http://www.ferrergrupo.com/Innovation_Innovacion-Pipeline-de-proyectos-ENG (accessed on 15 April 2013).
  20. Yamakawa, T.; Mitsuyama, J.; Hayashi, K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J. Antimicrob. Chemother. 2002, 49, 455–465. [Google Scholar] [CrossRef]
  21. Ferrer Internacional. Efficacy and safety of ozenoxacin 1% cream versus placebo in the treatment of patients with impetigo. Available online: http://clinicaltrials.gov/ct2/show/NCT01397461 (accessed on 13 April 2013).
  22. Kosowska-Shick, K.; Credito, K.; Pankuch, G.A.; Lin, G.; Bozdogan, B.; McGhee, P.; Dewasse, B.; Choi, D.-R.; Ryu, J.M.; Appelbaum, P.C. Antipneumococcal activity of DW-224a, a new quinolone, compared to those of eight other agents. Antimicrob. Agents Chemother. 2006, 50, 2064–2071. [Google Scholar] [CrossRef]
  23. Park, H.-S.; Kim, H.-J.; Seol, M.-J.; Choi, D.-R.; Choi, E.-C.; Kwak, J.-H. In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob. Agents Chemother. 2006, 50, 2261–2264. [Google Scholar] [CrossRef]
  24. Dong Wha Pharmaceutical Co. Ltd. A study to evaluate efficacy and safety profile of Zabofloxacin tablet 400 mg and moxifloxacin tablet 400 mg. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01658020 (accessed on 15 July 2013).
  25. Dong Wha Pharmaceutical Co. Ltd. A new quinolone antibiotic. Available online: http://www.dong-wha.co.kr/english/rnd/rnd02_03.asp (accessed on 15 April 2013).
  26. Remy, J.M.; Tow-Keogh, C.A.; McConnell, T.S.; Dalton, J.M.; DeVito, J.A. Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: Resistance selection and characterization. J. Antimicrob. Chemother. 2012, 67, 2814–2820. [Google Scholar] [CrossRef]
  27. Rib-X Pharmaceuticals. Delafloxacin. Available online: http://www.rib-x.com/pipeline/delafloxacin.php (accessed on 15 April 2013).
  28. Otsuka Pharmaceutical. Delafloxacin versus vancomycin and aztreonam for the treatment of acute bacterial skin and skin structure infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01811732 (accessed on 15 April 2013).
  29. Furiex Pharmaceuticals. Efficacy and safety study of JNJ-32729463 compared with moxifloxacin for the treatment of subjects requiring hospitalization for community-acquired bacterial pneumonia. Available online: http://clinicaltrials.gov/ct2/show/NCT01198626 (accessed on 13 April 2013).
  30. Furiex Pharmaceuticals. Efficacy and safety study of JNJ-32729463 for treating complicated skin and skin structure infections compared to linezolid (zyvox). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01128530 (accessed on 22 July 2013).
  31. Furiex. JNJ-Q2 best-in-class, broad-spectrum fluoroquinolone with potent MRSA coverage. Available online: http://www.furiex.com/wp-content/uploads/2011/07/JNJ-Q2_Info-Sheet-JUNE-2011.pdf (accessed on 13 April 2013).
  32. Furiex. Furiex receives qualified infectious disease product and fast track designations from the U.S. Food and Drug Administration for Avarofloxacin (JNJ-Q2). Available online: http://investor.furiex.com/releasedetail.cfm?ReleaseID=742926 (accessed on 13 April 2013).
  33. Biedenbach, D.J.; Farrell, D.J.; Flamm, R.K.; Liverman, L.C.; McIntyre, G.; Jones, R.N. Activity of JNJ-Q2, a new fluoroquinolone, tested against contemporary pathogens isolated from patients with community-acquired bacterial pneumonia. Int. J. Antimicrob. Agents 2012, 39, 321–325. [Google Scholar] [CrossRef]
  34. Covington, P.; Davenport, J.M.; Andrae, D.; O’Riordan, W.; Liverman, L.; McIntyre, G.; Almenoff, J. Randomized, double-blind, phase II, multicenter study evaluating the safety/ tolerability and efficacy of JNJ-Q2, a novel fluoroquinolone, compared with linezolid for treatment of acute bacterial skin and skin structure infection. Antimicrob. Agents Chemother. 2011, 55, 5790–5797. [Google Scholar] [CrossRef]
  35. Morrow, B.J.; He, W.; Amsler, K.M.; Foleno, B.D.; Macielag, M.J.; Lynch, A.S.; Bush, K. In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone. Antimicrob. Agents Chemother. 2010, 54, 1955–1964. [Google Scholar] [CrossRef]
  36. Durata Therapeutics, Inc. Finafloxacin for the treatment of cUTI and/or acute pyelonephritis. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01928433 (accessed on 28 September 2013).
  37. Merlion Pharma. A multi-dose, double-blind, double-dummy, active control, randomized clinical (Phase II) study of two dosing regimens of finafloxacin for the treatment of cUTI and/or acute pyelonephritis. Available online: http://www.clinicaltrialsregister.eu/ctr-search/trial/2011–006041–14/PL/ (accessed on 14 April 2013).
  38. Pharma, M. FDA Grants Qualified Infectious Disease Product Designation and Fast Track Status for MerLion Pharma’s Lead Antibacterial Candidate Finafloxacin; Merlion Pharma: Singapore, 2013; Volume 2013. [Google Scholar]
  39. Lemaire, S.; van Bambeke, F.; Tulkens, P.M. Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila. Int. J. Antimicrob. Agents 2011, 38, 52–59. [Google Scholar] [CrossRef]
  40. Appelbaum, P.C. 2012 and beyond: Potential for the start of a second pre-antibiotic era? J. Antimicrob. Chemother. 2012, 67, 2062–2068. [Google Scholar] [CrossRef]
  41. Wockhardt Limited. Phase II open label, multi-centeric clinical trial of oral WCK 2349 (1000 mg bid and 1200 mg bid) to evaluate safety and efficacy in the treatment of complicated skin and soft tissue infections caused by gram positive bacteria. Available online: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1797 (accessed on 15 April 2013).
  42. Wockhardt. New chemical entity pipeline. Available online: http://www.wockhardt.com/how-we-touch-lives/new-drug-discover.aspx (accessed on 15 April 2013).
  43. Peric, M.; Jacobs, M.R.; Appelbaum, P.C. Antianaerobic activity of a novel fluoroquinolone, WCK 771, compared to those of nine other agents. Antimicrob. Agents Chemother. 2004, 48, 3188–3192. [Google Scholar] [CrossRef]
  44. Kyorin. Kyorin—Main R&D Activities-1 (4 February 2013 Release). Available online: http://www.kyorin-pharm.co.jp/en/business/pdf/main_rd_activities_20130204_en.pdf (accessed on 4 February 2013).
  45. Kyorin. Drug discovery, development, and lcm with medical professionals and patients in mind. Available online: http://www.kyorin-gr.co.jp/en/business/gensen/r_and_d.shtml (accessed on 11 April 2013).
  46. Higuchi, S.; Onodera, Y.; Chiba, M.; Hoshino, K.; Gotoh, N. Potent in vitro antibacterial activity of DS-8587, a new generation of broad spectrum quinolone, against Acinetobacter baumannii. Antimicrob. Agents Chemother. 2013. [Google Scholar] [CrossRef]
  47. Daiichi Sankyo. Major R&D pipeline as of July, 2013. Available online: http://www.daiichisankyo.com/rd/pipeline/pdf/Pipeline_EN.pdf (accessed on 28 September 2013).
  48. Achillion Pharmaceuticals. About ACH-702. Available online: http://www.achillion.com/PL/pdf/04_ach_702_bg.pdf (accessed on 2 May 2013).
  49. Pucci, M.J.; Podos, S.D.; Thanassi, J.A.; Leggio, M.J.; Bradbury, B.J.; Deshpande, M. In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens. Antimicrob. Agents Chemother. 2011, 55, 2860–2871. [Google Scholar] [CrossRef]
  50. Achaogen. Study for the treatment of complicated urinary tract infection and acute pyelonephritis. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01096849 (accessed on 11 April 2013).
  51. Zhanel, G.G.; Lawson, C.D.; Zelenitsky, S.; Findlay, B.; Schweizer, F.; Adam, H.; Walkty, A.; Rubinstein, E.; Gin, A.S.; Hoban, D.J.; et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti-Infect. Ther. 2012, 10, 459–473. [Google Scholar] [CrossRef]
  52. Endimiani, A.; Hujer, K.M.; Hujer, A.M.; Armstrong, E.S.; Choudhary, Y.; Aggen, J.B.; Bonomo, R.A. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob. Agents Chemother. 2009, 53, 4504–4507. [Google Scholar]
  53. Achaogen. Achaogen pipeline. Available online: http://www.achaogen.com (accessed on 30 August 2012).
  54. Achaogen. Achaogen Awarded $60M Contract Option by BARDA for the Clinical Development of Plazomicin. Available online: http://www.achaogen.com/news/151/15 (accessed on 19 June 2013).
  55. Achaogen. Achaogen announces all objectives met in Phase 2 Plazomicin complicated urinary tract infections study and start of first-in-human study with ACHN-975. Available online: http://www.achaogen.com/uploads/news/id148/Achaogen_PressRelease_2012–05–15.pdf (accessed on 10 April 2013).
  56. Achaogen. Achaogen Announces Agreement with FDA on a Special Protocol Assessment for a Phase 3 Clinical Trial of Plazomicin to Treat Infections Caused by Carbapenem-Resistant Enterobacteriaceae (CRE); Achaogen: San Francisco, CA, USA, 2013. [Google Scholar]
  57. Achaogen. Next-generation aminoglycosides. Available online: http://www.achaogen.com/pipeline/next-generation-aminoglycosides (accessed on 6 December 2012).
  58. Maianti, J.P.; Aggen, J.B.; Dozzo, P.; Goldblum, A.A.; Hildebrandt, D.J.; Kane, T.R.; Gliedt, M.J.; Linsell, M.S.; Hanessian, S.; Giguere, A. Antibacterial Aminoglycoside Analogs. WO2011044498A1, 14 April 2011. [Google Scholar]
  59. Dozzo, P.; Goldblum, A.A.; Aggen, J.B. Antibacterial Aminoglycoside Analogs. WO2011044502A1, 14 April 2011. [Google Scholar]
  60. Aggen, J.B.; Goldblum, A.A.; Dozzo, P.; Hildebrandt, D.J.; Kane, T.R.; Gliedt, M.J.; Linsell, M.S. Antibacterial Aminoglycoside Analogs. WO2011044503A1, 14 April 2011. [Google Scholar]
  61. Aggen, J.B.; Dozzo, P.; Goldblum, A.A.; Hildebrandt, D.J.; Kane, T.R.; Gliedt, M.J.; Linsell, M.S. Antibacterial Aminoglycoside Analogs. WO2011044538A1, 14 April 2011. [Google Scholar]
  62. Aggen, J.B.; Dozzo, P.; Goldblum, A.A.; Hildebrandt, D.J.; Kane, T.R.; Gliedt, M.J.; Linsell, M.S. Antibacterial Aminoglycoside Analogs. WO2011044501A2, 14 April 2011. [Google Scholar]
  63. Goldblum, A.A.; Dozzo, P.; Kane, T.R.; Aggen, J.B.; Linsell, M.S.; Hildebrandt, D.J.; Gliedt, M.J. Antibacterial Aminoglycoside Analogs. US20120122809A1, 17 May 2012. [Google Scholar]
  64. Changzhou Fangyuan Pharmaceutical. Achievements Introduced. Available online: http://s2.shenjian.net/Cn_about_ID13.html (accessed on 7 April 2013).
  65. Changzhou Fangyuan Pharmaceutical. Jiangsu a semi-sinthetic antibiotic engeenering technology research center. Available online: http://s2.shenjian.net/Cn_about_ID13.html (accessed on 6 December 2012).
  66. Cempra Pharmaceuticals. Solithromycin (CEM-101). Available online: http://www.cempra.com/products/Solithromycin-cem-101/ (accessed on 15 April 2013).
  67. Cempra Pharmaceuticals. Efficacy and safety study of oral solithromycin (CEM-101) compared to oral moxifloxacin in treatment of patients with community-acquired bacterial pneumonia. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01756339 (accessed on 15 April 2013).
  68. Cempra Pharmaceuticals. Safety and efficacy study of single-dose oral CEM-101 in patients with uncomplicated urogenital gonorrhea. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01591447 (accessed on 15 April 2013).
  69. Lemaire, S.; van Bambeke, F.; Tulkens, P.M. Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 macrophages. Antimicrob. Agents Chemother. 2009, 53, 3734–3743. [Google Scholar]
  70. McGhee, P.; Clark, C.; Kosowska-Shick, K.M.; Nagai, K.; Dewasse, B.; Beachel, L.; Appelbaum, P.C. In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms. Antimicrob. Agents Chemother. 2010, 54, 230–238. [Google Scholar] [CrossRef]
  71. Fernandes, P.; Pereira, D.; Jamieson, B.; Keedy, K. Solithromycin: Macrolide antibiotic. Drugs Future 2011, 36, 751–758. [Google Scholar]
  72. Oldach, D.; Clark, K.; Schranz, J.; Das, A.; Craft, J.C.; Scott, D.; Jamieson, B.D.; Fernandes, P. Randomized, double-blind, multicenter phase 2 study comparing the efficacy and safety of oral solithromycin (CEM-101) to those of oral levofloxacin in the treatment of patients with community-acquired bacterial pneumonia. Antimicrob. Agents Chemother. 2013, 57, 2526–2534. [Google Scholar] [CrossRef]
  73. Cempra Pharmaceuticals. Preclinical programs—About macrolides. Available online: http://www.cempra.com/preclinical-programs/about-macrolides/ (accessed on 6 December 2012).
  74. Pereira, D.E. Hydrogen Bond Forming Fluoro Ketolides for Treating Diseases. WO2012034058A1, 15 March 2012. [Google Scholar]
  75. Enanta Pharmaceuticals. EDP-788/EDP-322. Available online: http://www.enanta.com/research/antibiotics/ (accessed on 11 April 2013).
  76. Enanta Pharmaceuticals. Enanta Pharmaceuticals Announces National Institute of Allergy and Infectious Diseases (NIAID) Will Fund Further Development of a Novel Bicyclolide; Business Wire: Watertown, NY, USA, 2013. [Google Scholar]
  77. Enanta Pharmaceuticals. Bicyclolide antibiotics. Available online: http://www.enanta.com/research/antibiotics/ (accessed on 6 December 2012).
  78. Enanta Pharmaceuticals. Enanta reports new macrolide-related drug class, bicyclolides, to combat hospital and community acquired superbug infections, including MRSA. Available online: http://www.prnewswire.com/news-releases/enanta-reports-new-macrolide-related-drug-class-bicyclolides-to-combat-hospital-and-community-acquired-superbug-infections-including-mrsa-57361732.html (accessed on 6 December 2012).
  79. Wang, G.; Xu, G.; Or, Y.S.; Gang, L.; Niu, D.; Fu, H.; Qui, Y.; Wang, Y.; Basayek, M.; Peng, Y.; et al. New 6–11 Bicyclic Macrolide Derivative Useful in Pharmaceutical Composition for Preventing and/or Treating Bacterial Infection in Humans. CN101955508-A, 26 January 2011. [Google Scholar]
  80. Kim, I.J.; Liu, T.; Long, J.; Wang, G.; Qiu, Y.; Kim, H.; Wang, Y.; Phan, L.T.; Or, Y.S. 6,11-Bridged Biaryl Macrolides. US2013165641-A1, 27 June 2013. [Google Scholar]
  81. Wockhardt. New chemical entities pipeline strategic focus on sepsis and antiinfectives. Available online: http://www.wockhardt.com/how-we-touch-lives/new-drug-discover.aspx (accessed on 4 April 2013).
  82. Wockhardt. Wockhardt annual report 2011–2012. Available online: http://www.wockhardt.com/pdf/Annual-Report-2011–2012-f932f.pdf (accessed on 4 April 2013).
  83. Rib-X Pharmaceuticals. Discovery programs—RX-02. Available online: http://www.rib-x.com/pipeline/discovery-programs.php (accessed on 12 July 2012).
  84. Vera-Cabrera, L.; Gonzalez, E.; Rendon, A.; Ocampo-Candiani, J.; Welsh, O.; Velazquez-Moreno, V.M.; Hak Choi, S.; Molina-Torres, C. In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis. Antimicrob. Agents Chemother. 2006, 50, 3170–3172. [Google Scholar] [CrossRef]
  85. Prokocimer, P.; Bien, P.; DeAnda, C.; Pillar, C.M.; Bartizal, K. In vitro activity and microbiological efficacy of Tedizolid (TR-700) against Gram-positive clinical isolates from a phase 2 study of oral Tedizolid phosphate (TR-701) in patients with complicated skin and skin structure infections. Antimicrob. Agents Chemother. 2012, 56, 4608–4613. [Google Scholar] [CrossRef]
  86. Prokocimer, P.; de Anda, C.; Fang, E.; Mehra, P.; Das, A. Tedizolid phosphate vs. linezolid for treatment of acute bacterial skin and skin structure infections: The establish-1 randomized trial. JAMA 2003, 309, 559–569. [Google Scholar] [CrossRef]
  87. Trius Therapeutics. TR-701 FA vs. linezolid for the treatment of acute bacterial skin and skin structure infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01421511 (accessed on 15 April 2013).
  88. Smith, L. Trius: Clinical trials show important differentiation of tedizolid from zyvox (TSRX, $6.48). Available online: http://smithonstocks.com/trius-clinical-trials-show-important-differentiation-of-tedizolid-from-zyvox-tsrx-6–48/ (accessed on 15 April 2013).
  89. Shapiro, S. Speculative strategies for new antibacterials: All roads should not lead to Rome. J. Antibiot. (Tokyo) 2013, 66, 371–386. [Google Scholar] [CrossRef]
  90. Actelion Pharmaceuticals. Cadazolid. Available online: http://www1.actelion.com/en/scientists/development-pipeline/phase-3/cadazolid.page (accessed on 10 August 2013).
  91. Chilton, C.H.; Crowther, G.S.; Baines, S.D.; Todhunter, S.L.; Freeman, J.; Locher, H.H.; Athanasiou, A.; Wilcox, M.H. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J. Antimicrob. Chemother. 2013. [Google Scholar] [CrossRef]
  92. Rempex Pharmaceuticals. ACT-179811 in patients with Clostridium difficile infection (CDI). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01222702 (accessed on 15 August 2013).
  93. Sutcliffe, J.A. Antibiotics in development targeting protein synthesis. Ann. NY Acad. Sci. 2011, 1241, 122–152. [Google Scholar] [CrossRef]
  94. Rib-X. Radezolid. Available online: http://www.rib-x.com/pipeline/radezolid.php#development (accessed on 14 April 2013).
  95. Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinone to treat pneumonia. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00640926 (accessed on 14 April 2013).
  96. Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinones to treat uncomplicated skin infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00646958 (accessed on 14 April 2013).
  97. Shaw, K.J.; Barbachyn, M.R. The oxazolidinones: Past, present, and future. Ann. NY Acad. Sci. 2011, 1241, 48–70. [Google Scholar] [CrossRef]
  98. Skripkin, E.; McConnell, T.S.; DeVito, J.; Lawrence, L.; Ippolito, J.A.; Duffy, E.M.; Sutcliffe, J.; Franceschi, F. Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob. Agents Chemother. 2008, 52, 3550–3557. [Google Scholar] [CrossRef]
  99. AstraZeneca. New tuberculosis drug trial begins in South Africa. Available online: http://www.astrazeneca.com/Research/news/Article/20121210--new-tuberculosis-drug-trial-begins-in-south-africa (accessed on 12 April 2013).
  100. Working Group on New TB Drugs. AZD5847 oxazolidinone. Available online: http://www.newtbdrugs.org/project.php?id=174 (accessed on 12 April 2013).
  101. National Institute of Allergy and Infectious Diseases (NIAID). Phase 2a EBA trial of AZD5847. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01516203 (accessed on 12 April 2013).
  102. Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: The drug development pipeline at a glance. Eur. J. Med. Chem. 2012, 51, 1–16. [Google Scholar] [CrossRef]
  103. Jeong, J.-W.; Jung, S.-J.; Lee, H.-H.; Kim, Y.-Z.; Park, T.-K.; Cho, Y.-L.; Chae, S.-E.; Baek, S.-Y.; Woo, S.-H.; Lee, H.-S.; et al. In vitro and In vivo activities of LCB01–0371, a new oxazolidinone. Antimicrob. Agents Chemother. 2010, 54, 5359–5362. [Google Scholar] [CrossRef]
  104. LegoChem Biosciences. Multiple ascendoing dose study for LCB01–0371. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01842516 (accessed on 15 August 2013).
  105. MicuRx Pharmaceuticals, Inc. MicuRx and Shanghai Zhangjiang biomedical industry venture capital partner to develop next-generation antibiotic MRX-I for Chinese market. Available online: http://www.micurx.com/doc/10-24-12%20JV-FINAL.doc (accessed on 11 April 2013).
  106. MicuRx Pharmaceuticals. Discovery and development. Available online: http://www.micurx.com/d1.htm (accessed on 12 December 2012).
  107. Paratek. About Paratek. Available online: http://www.paratekpharm.com/ (accessed on 15 January 2013).
  108. Paratek. Paratek Pharmaceuticals announces FDA Grant of Qualified Infectious Disease Product (QIDP) designation for its lead product candidate, Omadacycline—QIDP status designated for both intravenous and oral formulations. Available online: http://www.paratekpharm.com/press/010313%20Paratek%20QIDP%20Press%20Release.pdf (accessed on 15 April 2013).
  109. Tetraphase Pharmaceuticals. Tetraphase pipeline—Overview. Available online: http://tphase.com/pipeline/overview/default.cfm#tp271 (accessed on 10 April 2013).
  110. Tetraphase Pharmaceuticals. Study to compare TP-434 and Ertapenem in CA complicated intra-abdominal infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01265784 (accessed on 14 April 2013).
  111. Grossman, T.H.; Starosta, A.L.; Fyfe, C.; O’Brien, W.; Rothstein, D.M.; Mikolajka, A.; Wilson, D.N.; Sutcliffe, J.A. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob. Agents Chemother. 2012, 56, 2559–2564. [Google Scholar] [CrossRef]
  112. Ronn, M.; Zhu, Z.; Hogan, P.C.; Zhang, W.-Y.; Niu, J.; Katz, C.E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D.K.; et al. Process R&D of Eravacycline: The first fully synthetic fluorocycline in clinical development. Org. Process Res. Dev. 2013, 17, 838–845. [Google Scholar]
  113. Cynamon, M.; Jureller, J.; Desai, B.; Ramachandran, K.; Sklaney, M.; Grossman, T.H. In vitro activity of TP-271 against Mycobacterium abscessus, Mycobacterium fortuitum, and Nocardia Species. Antimicrob. Agents Chemother. 2012, 56, 3986–3988. [Google Scholar] [CrossRef]
  114. Grossman, T.; Hunt, D.; Heine III, H.; Sutcliffe, J. TP-271, a novel oral fluorocycline for community-acquired respiratory and biothreat pathogens. In Proceedings of 50th International Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, USA, 12–15 September 2010.
  115. Tetraphase. Our technology. Available online: http://tphase.com/technology/our_technology/default.cfm (accessed on 11 April 2013).
  116. Chen, C.-L.; Clark, R.B.; Deng, Y.; Plamondon, L.; Sun, C.; Xiao, X.-Y. Tetracycline Analogs. WO2012021712A1, 16 February 2012. [Google Scholar]
  117. Xiao, X.-Y.; Clark, R.; Hunt, D.; Roenn, M.; Plamondon, L.; He, M.; Sutcliffe, J.; Grossman, T. Polycyclic Tetracycline Compounds. WO2011123536A1, 6 October 2011. [Google Scholar]
  118. Deng, Y.; Plamondon, L.; Sun, C.; Xiao, X.-Y.; Zhou, J.; Sutcliffe, J.A.; Ronn, M.P. Tetracycline Compounds. WO2011025982A2, 3 March 2011. [Google Scholar]
  119. Nabriva. Pleuromutilins. Available online: http://www.nabriva.com/programs/pleuromutilins/ (accessed on 7 December 2012).
  120. Forest Laboratories. Our pipeline: Solid, and set for further growth. Available online: http://www.frx.com/research/pipeline.aspx (accessed on 13 April 2013).
  121. Sader, H.S.; Biedenbach, D.J.; Paukner, S.; Ivezic-Schoenfeld, Z.; Jones, R.N. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 2012, 56, 1619–1623. [Google Scholar] [CrossRef]
  122. Sader, H.S.; Paukner, S.; Ivezic-Schoenfeld, Z.; Biedenbach, D.J.; Schmitz, F.J.; Jones, R.N. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J. Antimicrob. Chemother. 2012, 67, 1170–1175. [Google Scholar] [CrossRef]
  123. Nabriva Therapeutics AG. Study comparing the safety and efficacy of two doses of BC-3781 vs. vancomycin in patients with acute bacterial skin and skin structure infection (ABSSSI). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01119105 (accessed on 13 April 2013).
  124. Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci. 2011, 1241, 71–81. [Google Scholar] [CrossRef]
  125. Riedl, R.; Thirring, K.; Heilmayer, W. Pleuromutilin Derivatives for Use in the Treatment of Diseases Mediated by Microbes. WO2012031307A1, 15 March 2012. [Google Scholar]
  126. Mang, R.; Thirring, K.; Heilmayer, W. Pleuromutilin Derivatives for Use in the Treatment of Diseases Mediated by Microbes. EP2433926A1, 28 March 2012. [Google Scholar]
  127. Heilmayer, W.; Mang, R.; Badegruber, R.; Stickmann, D.; Novak, R.; Ferencic, M.; Bulusu, A.R.C.M. Pleuromutilin Derivatives for the Treatment of Diseases Mediated by Microbes. MX2010009451A, 27 February 2012. [Google Scholar]
  128. García-Sánchez, J.E.; García-Merino, E.; Martín-del-Rey, Á.; García-Sánchez, E. Antibiotheraphy in the 21st century, antibacterials for the second decade. Posibilities or realities in the future? Rev. Esp. Quimioter. 2012, 25, 100–121. [Google Scholar]
  129. Cubist Pharmaceuticals. Safety and efficacy of intravenous CXA-201 and intravenous meropenem in complicated intraabdominal infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01445665 (accessed on 15 April 2013).
  130. Cubist Pharmaceuticals. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous levofloxacin in complicated urinary tract infection, including pyelonephritis. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01345955 (accessed on 15 April 2013).
  131. Cubist Pharmaceuticals. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous meropenem in complicated intraabdominal infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01445678 (accessed on 15 April 2013).
  132. Cubist Pharmaceuticals. Ceftolozane/tazobactam overview. Available online: http://www.cubist.com/products/cxa_201 (accessed on 15 August 2013).
  133. Basilea Pharmaceutica. Basilea Awarded Contract by BARDA of Up to USD 89 Million for the Development of Its Novel Antibiotic BAL30072; Basilea Pharmaceutica Ltd.: Basel, Switzerland, 2013; Volume 2013. [Google Scholar]
  134. Page, M.G.P.; Dantier, C.; Desarbre, E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative bacilli. Antimicrob. Agents Chemother. 2010, 54, 2291–2302. [Google Scholar] [CrossRef]
  135. Basilea Pharmaceutica. Basilea Pharmaceutica Ltd. Annual Report 2012. Available online: http://annualreport.basilea.com/downloads/Basilea_AR12_E.pdf (accessed on 11 April 2013).
  136. Shionogi. Pipeline (as of August 2013). Available online: http://www.shionogi.co.jp/en/company/pmrltj0000000u4v-att/e_kaihatsu.pdf (accessed on 4 August 2013).
  137. Shionogi. Research and development at Shionogi. Available online: http://www.shionogi.com/pdf/RDmeeting2012.pdf (accessed on 12 April 2013).
  138. GlaxoSmithKline. GlaxoSmithKline product development pipeline 2013. Available online: http://www.gsk.com/content/dam/gsk/globals/documents/pdf/GSK%202013%20Pipeline.pdf (accessed on 11 April 2013).
  139. Cubist Pharmaceuticals. Cubist to Feature Antibiotic Development Programs at 52nd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Available online: http://www.businesswire.com/news/home/20120906005268/en/Cubist-Feature-Antibiotic-Development-Programs-52nd-Annual (accessed on 8 April 2013).
  140. Joo, H.; Choi, W.-B.; Kim, D.-I.; Kowalik, S.; Mao, E.; Li, Y.; Liu, S.; Hager, M.W. FSI-1671, a Novel Anti-Acinetobacter Carbapenem; in vitro Activity of FSI-1671 and FSI-1671/Sulbactam against MDR-A.baumannii. In Proceedings of 53rd International Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 11 September 2013.
  141. Joo, H.; Choi, W.-B.; Kim, D.-I.; Kowalik, E.; Hager, M.W.; Mao, S.; Li, Y.; Liu, S. FSI-1671, a Novel Anti-Acinetobacter Carbapenem; in vivo Efficacy against Carbapenem-Resistance Gram-Negative Bacterial Infection. In Proceedings of 53rd International Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 11 September 2013.
  142. AstraZeneca. Compare ceftazidime-avibactam and doripenem followed by oral therapy for hospitalized adults with complicated UTIs (Urinary Tract Infections). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01599806 (accessed on 15 April 2013).
  143. AstraZeneca. Our Pipeline—Development pipeline as at 31 December 2012. Available online: http://www.astrazeneca.com/Research/Our-pipeline-summary (accessed on 12 April 2013).
  144. AstraZeneca; Cerexa, Inc. Ceftazidime-Avibactam for the treatment of infections due to ceftazidime resistant pathogens. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01644643 (accessed on 15 April 2013).
  145. AstraZeneca; Cerexa, Inc. Ceftazidime-Avibactam compared with doripenem followed by oral therapy for hospitalized adults with complicated UTIs (Urinary Tract Infections). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01595438 (accessed on 15 April 2013).
  146. AstraZeneca; Cerexa, Inc. A study comparing Ceftazidime-Avibactam + Metronidazole versus Meropenem in adults with complicated intra-abdominal infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01500239 (accessed on 15 April 2013).
  147. Coleman, K. Diazabicyclooctanes (DBOs): A potent new class of non-beta-lactam beta-lactamase inhibitors. Curr. Opin. Microbiol. 2011, 14, 550–555. [Google Scholar] [CrossRef]
  148. Shlaes, D.M. New β-lactam-β-lactamase inhibitor combinations in clinical development. Ann. NY Acad. Sci. 2013, 1277, 105–114. [Google Scholar] [CrossRef]
  149. Cerexa, Inc. Comparative study of coadministered ceftaroline fosamil and NXL104 vs. intravenous doripenem in adult subjects with complicated Urinary Tract Infections. Available online: http://clinicaltrials.gov/ct2/show/NCT01281462 (accessed on 13 April 2013).
  150. Riccobene, T.A.; Su, S.F.; Rank, D. Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects. Antimicrob. Agents Chemother. 2013, 57, 1496–1504. [Google Scholar] [CrossRef]
  151. Castanheira, M.; Sader, H.S.; Farrell, D.J.; Mendes, R.E.; Jones, R.N. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various Staphylococcal cassette chromosome mec types. Antimicrob. Agents Chemother. 2012, 56, 4779–4785. [Google Scholar] [CrossRef]
  152. Merck. Merck pipeline. Available online: http://www.merck.com/research/pipeline/home.html (accessed on 22 February 2013).
  153. Merck & Co. Inc. Study of the safety, tolerability, and efficacy of MK-7655 + Imipenem/ Cilastatin versus Imipenem/Cilastatin Alone for the treatment of complicated Urinary Tract Infection (cUTI) (MK-7655–003 AM4). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01505634 (accessed on 14 April 2013).
  154. Merck & Co. Inc. Study of the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/ Cilastatin versus Imipenem/Cilastatin Alone to Treat Complicated Intra-Abdominal Infection [cIAI] (MK-7655–004 AM2). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01506271 (accessed on 14 April 2013).
  155. Hirsch, E.B.; Ledesma, K.R.; Chang, K.T.; Schwartz, M.S.; Motyl, M.R.; Tam, V.H. In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 2012, 56, 3753–3757. [Google Scholar] [CrossRef]
  156. Mendes, R.E.; Rhomberg, P.R.; Becker, H.K.; Jones, R.N. Activity of β-Lactam agents tested in combination with novel β-lactamase inhibitor compounds against enterobacteriaceae producing extended-spectrum β-Lactamases. In Proceedings of 53nd International Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 12 September 2013.
  157. Fedora Pharmaceuticals. Fedora Pharmaceuticals Demonstrates that FPI-1465 Increases Activity of Certain Antibiotics against Drug-Resistant Bacteria; Fedora Pharmaceuticals: Edmonton, Canada, 2013. [Google Scholar]
  158. Shlaes, D.M. Antibiotics, ICAAC and Bronchitis. Available online: http://antibiotics-theperfectstorm.blogspot.com.br/2012/09/antibiotics-icaac-and-bronchitis.html (accessed on 12 April 2013).
  159. Rempex Abstracts were Published as Part of the 52nd ICAAC, September 2012, San Francisco, CA, USA. Available online: http://www.rempexpharma.com/pubs/icaac2012abstracts (accessed on 11 April 2013).
  160. Rempex Pharmaceuticals. Safety Study of Intravenous Biapenem (RPX2003) and RPX7009 Given Alone and in Combination. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01772836 (accessed on 12 April 2013).
  161. Rempex Pharmaceuticals. Safety, tolerability, pharmacokinetics of intravenous RPX7009 in healthy adult subjects. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01751269 (accessed on 12 April 2013).
  162. Martell, L.A.; Rahil, G.; Vaisburg, A.; Young, K.; Hickey, E.; Hermes, J.; Dininno, F.; Besterman, J.M. A Novel Beta-Lactamase Inhibitor Potentiates and Extends the Antibacterial Activity of Imipenem against β-Lactam-Resistant P. aeruginosa and K. pneumoniae. In Proceedings of 49th ICAAC Annual Meeting, San Francisco, CA, USA, 14 September 2009.
  163. Mirati Therapeutics. MG96077. Available online: http://mirati.com/other-pipeline-assets/mg96077 (accessed on 9 July 2013).
  164. Durata Therapeutics, Inc. Efficacy and safety of dalbavancin for the treatment of acute bacterial skin and skin structure infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01431339 (accessed on 13 April 2013).
  165. Durata Therapeutics. Product pipeline dalbavancin overview. Available online: http://www.duratatherapeutics.com/product-pipeline/dalbavancin/overview (accessed on 15 April 2013).
  166. Durata Therapeutics. Efficacy and Safety of Dalbavancin for the Treatment of ABSSSI. Available online: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-024042-30/DE/ (accessed on 14 April 2013).
  167. Durata Therapeutics. Durata therapeutics announces preliminary, topline Phase 3 clinical trial results for dalbavancin in the treatment of ABSSSI. Available online: http://content.stockpr.com/_news/duratatherapeutics/2013-02-25_Durata_Therapeutics_Announces_Preliminary_Topline_364.pdf (accessed on 15 April 2013).
  168. Durata Therapeutics. Durata therapeutics meets primary endpoints for EMA review in Phase 3 clinical trial. Available online: http://content.stockpr.com/_news/duratatherapeutics/2013-01-04_Durata_Therapeutics_Meets_Primary_Endpoints_for_EM_343.pdf (accessed on 15 April 2013).
  169. The Medicines Company. Evaluation of the effect of an investigational antibiotic (Oritavancin) in the treatment of skin and skin structure infections compared to a commonly used antibiotic. Available online: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-021720-10/GB/ (accessed on 15 April 2013).
  170. The Medicines Company. Oritavancin versus IV vancomycin for the treatment of patients with acute bacterial skin and skin structure infection (SOLO I). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01252719 (accessed on 15 April 2013).
  171. The Medicines Company. Oritavancin versus IV vancomycin for the treatment of patients with acute bacterial skin and skin structure infection (SOLO II). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01252732 (accessed on 15 April 2013).
  172. The Medicines Company. Product Development is Innovation. Available online: http://www.themedicinescompany.com/page/pipeline (accessed on 15 April 2013).
  173. Karaoui, L.R.; El-Lababidi, R.; Chahine, E.B. Oritavancin: An investigational lipoglycopeptide antibiotic. Am. J. Health Syst. Pharm. 2013, 70, 23–33. [Google Scholar] [CrossRef]
  174. Johnson, A.P. New antibiotics for selective treatment of gastrointestinal infection caused by Clostridium difficile. Expert Opin. Ther. Pat. 2010, 20, 1389–1399. [Google Scholar] [CrossRef]
  175. Vaara, M.; Sader, H.S.; Rhomberg, P.R.; Jones, R.N.; Vaara, T. Antimicrobial activity of the novel polymyxin derivative NAB739 tested against Gram-negative pathogens. J. Antimicrob. Chemother. 2013, 68, 636–639. [Google Scholar] [CrossRef]
  176. Northern Antibiotics. Northern antibiotics fights against multi-resistant gram-negatives. Available online: http://www.northernantibiotics.com/index2.php?pageid=3&lang=em (accessed on 9 April 2013).
  177. Vaara, M.; Vaara, T. Novel derivatives of polymyxin B, a review on the NAB compounds. Available online: http://www.northernantibiotics.com/kuvat/NAB%20Technical%20Info%20Sheet%20Nov%202010.pdf (accessed on 9 April 2013).
  178. Kadar, B.; Kocsis, B.; Nagy, K.; Szabo, D. The renaissance of polymyxins. Curr. Med. Chem. 2013, 20, 3759–3773. [Google Scholar] [CrossRef]
  179. Vaara, M. Novel derivatives of polymyxins. J. Antimicrob. Chemother. 2013, 68, 1213–1219. [Google Scholar] [CrossRef]
  180. Cubist Pharmaceuticals. Cubist products and pipeline. Available online: http://www.cubist.com/products/ (accessed on 15 April 2013).
  181. Cubist Pharmaceuticals. Study of CB-183,315 in patients with Clostridium difficile associated diarrhea. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01597505 (accessed on 15 April 2013).
  182. Cubist Pharmaceuticals. A study of CB-183,315 in patients with Clostridium difficile associated diarrhea. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01598311 (accessed on 15 April 2013).
  183. Mascio, C.T.M.; Mortin, L.I.; Howland, K.T.; van, P.A.D.G.; Zhang, S.; Arya, A.; Chuong, C.L.; Kang, C.; Li, T.; Silverman, J.A. In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. Antimicrob. Agents Chemother. 2012, 56, 5023–5030. [Google Scholar] [CrossRef]
  184. Kato, A.; Nakaya, S.; Ohashi, Y.; Hirata, H.; Fujii, K.; Harada, K.-I. WAP-8294A2, a novel anti-MRSA antibiotic produced by Lysobacter sp. J. Am. Chem. Soc. 1997, 119, 6680–6681. [Google Scholar] [CrossRef]
  185. Kato, A.; Hirata, H.; Ohashi, Y.; Fujii, K.; Mori, K.; Harada, K.I. A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS. J. Antibiot. (Tokyo) 2011, 64, 373–379. [Google Scholar] [CrossRef]
  186. Pharma Japan. aRigen licenses novel anti-MRSA to GCC in South Korea. Available online: http://www.pharma-japan.com/ (accessed on 15 April 2013).
  187. Emrich, N.-C.; Heisig, A.; Stubbings, W.; Labischinski, H.; Heisig, P. Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations of defined mechanisms of fluoroquinolone resistance. J. Antimicrob. Chemother. 2010, 65, 2530–2533. [Google Scholar] [CrossRef]
  188. Stubbings, W.; Leow, P.; Yong, G.C.; Goh, F.; Körber-Irrgang, B.; Kresken, M.; Endermann, R.; Labischinski, H. In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. Antimicrob. Agents Chemother. 2011, 55, 4394–4397. [Google Scholar] [CrossRef]
  189. Bhagwat, S.S.; Mundkur, L.A.; Gupte, S.V.; Patel, M.V.; Khorakiwala, H.F. The anti-methicillin-resistant Staphylococcus aureus quinolone WCK 771 has potent activity against sequentially selected mutants, has a narrow mutant selection window against quinolone-resistant Staphylococcus aureus, and preferentially targets DNA gyrase. Antimicrob. Agents Chemother. 2006, 50, 3568–3579. [Google Scholar] [CrossRef]
  190. Bhagwat, S.S.; McGhee, P.; Kosowska-Shick, K.; Patel, M.V.; Appelbaum, P.C. In vitro activity of the quinolone WCK 771 against recent U.S. hospital and community-acquired Staphylococcus aureus pathogens with various resistance types. Antimicrob. Agents Chemother. 2009, 53, 811–813. [Google Scholar] [CrossRef]
  191. Zhu, D.; Hoshino, Y.K.K. DS-8587, A new generation of broad spectrum quinolone: In vitro antibacterial activities against Chinese clinical isolates. In Proceedings of 52nd International Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 12 September 2012.
  192. Achillion Pharmaceuticals, Inc. SEC filling form 10-Q quarterly report filed August 7, 2013. Available online: http://ir.achillion.com/secfiling.cfm?filingID=1193125–13–324297 (accessed on 28 September 2013).
  193. Reyes, N.; Aggen, J.B.; Kostrub, C.F. In vivo efficacy of the novel aminoglycoside ACHN-490 in murine infection models. Antimicrob. Agents Chemother. 2011, 55, 1728–1733. [Google Scholar] [CrossRef]
  194. Cass, R.T.; Brooks, C.D.; Havrilla, N.A.; Tack, K.J.; Borin, M.T.; Young, D.; Bruss, J.B. Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob. Agents Chemother. 2011, 55, 5874–5880. [Google Scholar] [CrossRef]
  195. Basilea Pharmaceutica. Exploratory programs. Available online: http://www.basilea.com/Research/Anti-infectives-research/ (accessed on 6 December 2012).
  196. Trius Therapeutics. TR-701 FA vs. linezolid for the treatment of acute bacterial skin and skin structure infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01170221 (accessed on 15 April 2013).
  197. Michalska, K.; Karpiuk, I.; Król, M.; Tyski, S. Recent development of potent analogues of oxazolidinone antibacterial agents. Biorg. Med. Chem. 2013, 21, 577–591. [Google Scholar] [CrossRef]
  198. Cubist Pharmaceuticals. Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections; Cubist Pharmaceuticals: Lexington, MA, USA.
  199. Noel, G.J.; Draper, M.P.; Hait, H.; Tanaka, S.K.; Arbeit, R.D. A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob. Agents Chemother. 2012, 56, 5650–5654. [Google Scholar] [CrossRef]
  200. Paratek Pharmaceuticals, Inc. Form S-1 Registration Statement under the Securities Act of 1933—Paratek Pharmaceuticals, Inc. Available online: http://www.sec.gov/Archives/edgar/data/1037643/000119312512406909/d386058ds1.htm#toc386058_10 (accessed on 5 August 2013).
  201. Tetraphase Pharmaceuticals. Efficacy and safety study of eravacycline compared with ertapenem in complicated intra-abdominal infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01844856 (accessed on 10 August 2013).
  202. Tetraphase Pharmaceuticals. Tetraphase Outlines Plans for Phase 3 Clinical Trial of Eravacycline IV/Oral in Complicated Urinary Tract Infections; Tetraphase Pharmaceuticals: Watertown, MA, USA, 2013. [Google Scholar]
  203. Nabriva. Nabriva Therapeutics Retains BC-3781 Rights as Forest Collaboration Elapses; Nabriva: Vienna, Austria, 2013; Volume 2013. [Google Scholar]
  204. Hornsey, M.; Phee, L.; Stubbings, W.; Wareham, D.W. In vitro activity of the novel monosulfactam BAL30072 alone and in combination with meropenem versus a diverse collection of important Gram-negative pathogens. Int. J. Antimicrob. Agents 2013, 42, 343–346. [Google Scholar] [CrossRef]
  205. Sader, H.S.; Rhomberg, P.R.; Farrell, D.J.; Jones, R.N. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with Tazobactam against enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob. Agents Chemother. 2011, 55, 2390–2394. [Google Scholar] [CrossRef]
  206. Zhang, S.; Chuong, L.I.M.C.; Khang, I.C.; Alsup, A.; Li, T.; Arya, A.; He, Y.; Yin, N.; Rock, J.; Abel, C.; et al. In Vivo efficacy of CB-027 against methicillin-resistant Staphylococcus aureus, and ceftazidime-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae infections in mice. In Proceedings of 52nd International Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 10 September 2012.
  207. Lucasti, C.; Popescu, I.; Ramesh, M.K.; Lipka, J.; Sable, C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: Results of a randomized, double-blind, Phase II trial. J. Antimicrob. Chemother. 2013, 68, 1183–1192. [Google Scholar] [CrossRef]
  208. Zhanel, G.; Lawson, C.; Adam, H.; Schweizer, F.; Zelenitsky, S.; Lagacé-Wiens, P.; Denisuik, A.; Rubinstein, E.; Gin, A.; Hoban, D.; et al. Ceftazidime-avibactam: A novel cephalosporin/ β-lactamase inhibitor combination. Drugs 2013, 73, 159–177. [Google Scholar] [CrossRef]
  209. Pucci, M.J.; Bush, K. Investigational antimicrobial agents of 2013. Clin. Microbiol. Rev. 2013, 26, 792–821. [Google Scholar] [CrossRef]
  210. Livermore, D.M.; Warner, M.; Mushtaq, S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2013, 68, 2286–2290. [Google Scholar]
  211. Maiti, S.N.; Ling, D.N.R.; Ha, C.M.; Ganguly, B.; Ou, L.; Shan, R.; Singh, R.; Kully, M.; Khan, J.; Salama, S.M.; et al. Design, synthesis and structure activity relationship of novel substituted amides containing diaza bicyclic heterocyclic compounds as broad-spectrum β-lactamase inhibitors. In Proceedings of 53nd International Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 12 September 2013.
  212. Zhanel, G.G.; Calic, D.; Schweizer, F.; Zelenitsky, S.; Adam, H.; Lagacé-Wiens, P.R.S.; Rubinstein, E.; Gin, A.S.; Hoban, D.J.; Karlowsky, J.A. New lipoglycopeptides: A comparative review of Dalbavancin, Oritavancin and Telavancin. Drugs 2010, 70, 859–886. [Google Scholar] [CrossRef]
  213. The Medicines Company. FDA Grants QIDP designation to the medicines company’s investigational antibiotic oritavancin. Available online: http://ir.themedicinescompany.com/phoenix.zhtml?c=122204&p=irol-newsArticle&ID=1875172&highlight= (accessed on 12 November 2013).
  214. Goodman, L.S.; Gilman, A. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th ed.; McGraw-Hill Professional: Nova York, NY, USA, 2011; Volume 2, p. 1808. [Google Scholar]

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De Souza Mendes, C.D.; De Souza Antunes, A.M. Pipeline of Known Chemical Classes of Antibiotics. Antibiotics 2013, 2, 500-534. https://doi.org/10.3390/antibiotics2040500

AMA Style

De Souza Mendes CD, De Souza Antunes AM. Pipeline of Known Chemical Classes of Antibiotics. Antibiotics. 2013; 2(4):500-534. https://doi.org/10.3390/antibiotics2040500

Chicago/Turabian Style

De Souza Mendes, Cristina D'Urso, and Adelaide Maria De Souza Antunes. 2013. "Pipeline of Known Chemical Classes of Antibiotics" Antibiotics 2, no. 4: 500-534. https://doi.org/10.3390/antibiotics2040500

APA Style

De Souza Mendes, C. D., & De Souza Antunes, A. M. (2013). Pipeline of Known Chemical Classes of Antibiotics. Antibiotics, 2(4), 500-534. https://doi.org/10.3390/antibiotics2040500

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