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Antibiotics, Volume 7, Issue 2 (June 2018)

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Open AccessArticle In Vitro Synergism of Silver Nanoparticles with Antibiotics as an Alternative Treatment in Multiresistant Uropathogens
Antibiotics 2018, 7(2), 50; https://doi.org/10.3390/antibiotics7020050
Received: 16 March 2018 / Revised: 10 June 2018 / Accepted: 14 June 2018 / Published: 19 June 2018
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Abstract
The increase in the prevalence of bacterial resistance to antibiotics has become one of the main health problems worldwide, thus threatening the era of antibiotics most frequently used in the treatment of infections. The need to develop new therapeutic strategies against multidrug resistant
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The increase in the prevalence of bacterial resistance to antibiotics has become one of the main health problems worldwide, thus threatening the era of antibiotics most frequently used in the treatment of infections. The need to develop new therapeutic strategies against multidrug resistant microorganisms, such as the combination of selected antimicrobials, can be considered as a suitable alternative. The in vitro activities of two groups of conventional antimicrobial agents alone and in combination with silver nanoparticles (AgNPs) were investigated against a set of ten multidrug resistant clinical isolate and two references strains by MIC assays and checkerboard testing, as well as their cytotoxicity, which was evaluated on human fibroblasts by MTT assay at the same concentration of the antimicrobial agents alone and in combination. Interesting results were achieved when the AgNPs and their combinations were characterized by Dynamic Light Scattering (DLS), Zeta Potential, Transmission Electron Microscopy (TEM), UV–visible spectroscopy and Fourier Transforms Infrared (FTIR) spectroscopy. The in vitro activities of ampicillin, in combination with AgNPs, against the 12 microorganisms showed one Synergy, seven Partial Synergy and four Additive effects, while the results with amikacin and AgNPs showed three Synergy, eight Partial Synergy and one Additive effects. The cytotoxic effect at these concentrations presented a statistically significant decrease of their cytotoxicity (p < 0.05). These results indicate that infections caused by multidrug resistant microorganisms could be treated using a synergistic combination of antimicrobial drugs and AgNPs. Further studies are necessary to evaluate the specific mechanisms of action, which could help predict undesirable off-target interactions, suggest ways of regulating a drug’s activity, and identify novel therapeutic agents in this health problem. Full article
(This article belongs to the Special Issue Silver-Based Antimicrobials)
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Open AccessReview Future Prospects for Neisseria gonorrhoeae Treatment
Antibiotics 2018, 7(2), 49; https://doi.org/10.3390/antibiotics7020049
Received: 22 May 2018 / Revised: 8 June 2018 / Accepted: 14 June 2018 / Published: 15 June 2018
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Abstract
Gonorrhea is a sexually transmitted disease with a high morbidity burden. Incidence of this disease is rising due to the increasing number of antibiotic-resistant strains. Neisseria gonorrhoeae has shown an extraordinary ability to develop resistance to all antimicrobials introduced for its treatment. In
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Gonorrhea is a sexually transmitted disease with a high morbidity burden. Incidence of this disease is rising due to the increasing number of antibiotic-resistant strains. Neisseria gonorrhoeae has shown an extraordinary ability to develop resistance to all antimicrobials introduced for its treatment. In fact, it was recently classified as a “Priority 2” microorganism in the World Health Organization (WHO) Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery and Development of New Antibiotics. Seeing as there is no gonococcal vaccine, control of the disease relies entirely on prevention, diagnosis, and, especially, antibiotic treatment. Different health organizations worldwide have established treatment guidelines against gonorrhea, mostly consisting of dual therapy with a single oral or intramuscular dose. However, gonococci continue to develop resistances to all antibiotics introduced for treatment. In fact, the first strain of super-resistant N.gonorrhoeae was recently detected in the United Kingdom, which was resistant to ceftriaxone and azithromycin. The increase in the detection of resistant gonococci may lead to a situation where gonorrhea becomes untreatable. Seeing as drug resistance appears to be unstoppable, new treatment options are necessary in order to control the disease. Three approaches are currently being followed for the development of new therapies against drug-resistant gonococci: (1) novel combinations of already existing antibiotics; (2) development of new antibiotics; and (3) development of alternative therapies which might slow down the appearance of resistances. N. gonorrhoeae is a public health threat due to the increasing number of antibiotic-resistant strains. Current treatment guidelines are already being challenged by this superbug. This has led the scientific community to develop new antibiotics and alternative therapies in order to control this disease. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)
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Open AccessArticle Neisseria gonorrhoeae Aggregation Reduces Its Ceftriaxone Susceptibility
Antibiotics 2018, 7(2), 48; https://doi.org/10.3390/antibiotics7020048
Received: 6 March 2018 / Revised: 25 May 2018 / Accepted: 14 June 2018 / Published: 15 June 2018
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Abstract
Antibiotic resistance in Neisseria gonorrhoeae (GC) has become an emerging threat worldwide and heightens the need for monitoring treatment failures. N. gonorrhoeae, a gram-negative bacterium responsible for gonorrhea, infects humans exclusively and can form aggregates during infection. While minimal inhibitory concentration (MIC)
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Antibiotic resistance in Neisseria gonorrhoeae (GC) has become an emerging threat worldwide and heightens the need for monitoring treatment failures. N. gonorrhoeae, a gram-negative bacterium responsible for gonorrhea, infects humans exclusively and can form aggregates during infection. While minimal inhibitory concentration (MIC) tests are often used for determining antibiotic resistance development and treatment, the knowledge of the true MIC in individual patients and how it relates to this laboratory measure is not known. We examined the effect of aggregation on GC antibiotic susceptibility and the relationship between bacterial aggregate size and their antibiotic susceptibility. Aggregated GC have a higher survival rate when treated with ceftriaxone than non-aggregated GC, with bacteria in the core of the aggregates surviving the treatment. GC lacking opacity-associated protein or pili, or expressing a truncated lipooligosaccharide, three surface molecules that mediate GC-GC interactions, reduce both aggregation and ceftriaxone survival. This study demonstrates that the aggregation of N. gonorrhoeae can reduce the susceptibility to antibiotics, and suggests that antibiotic utilization can select for GC surface molecules that promote aggregation which in turn drive pathogen evolution. Inhibiting aggregation may be a potential way of increasing the efficacy of ceftriaxone treatment, consequently reducing treatment failure. Full article
(This article belongs to the Special Issue Multi-Drug Resistant Neisseria gonorrhoeae)
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Open AccessArticle Novel Polyethers from Screening Actinoallomurus spp.
Antibiotics 2018, 7(2), 47; https://doi.org/10.3390/antibiotics7020047
Received: 1 May 2018 / Revised: 12 June 2018 / Accepted: 13 June 2018 / Published: 14 June 2018
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Abstract
In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus Actinoallomurus for their production of antibacterial compounds. When grown under
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In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus Actinoallomurus for their production of antibacterial compounds. When grown under just one condition, about half of the strains produced an extract that was able to inhibit growth of Staphylococcus aureus. We report here on the metabolites produced by 37 strains. In addition to previously reported aminocoumarins, lantibiotics and aromatic polyketides, we described two novel and structurally unrelated polyethers, designated α-770 and α-823. While we identified only one producer strain of the former polyether, 10 independent Actinoallomurus isolates were found to produce α-823, with the same molecule as main congener. Remarkably, production of α-823 was associated with a common lineage within Actinoallomurus, which includes A. fulvus and A. amamiensis. All polyether producers were isolated from soil samples collected in tropical parts of the world. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Iron Oxide Nanoparticles for Biomedical Applications: A Perspective on Synthesis, Drugs, Antimicrobial Activity, and Toxicity
Antibiotics 2018, 7(2), 46; https://doi.org/10.3390/antibiotics7020046
Received: 16 April 2018 / Revised: 1 June 2018 / Accepted: 7 June 2018 / Published: 9 June 2018
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Abstract
Medical applications and biotechnological advances, including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, have strongly benefited from employing iron oxide nanoparticles (IONPs) due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a
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Medical applications and biotechnological advances, including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, have strongly benefited from employing iron oxide nanoparticles (IONPs) due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a biocompatible coating. Ongoing research efforts focus on reducing drug concentration, toxicity, and other side effects, while increasing efficacy of IONPs-based treatments. This review highlights the methods of synthesis and presents the most recent reports in the literature regarding advances in drug delivery using IONPs-based systems, as well as their antimicrobial activity against different microorganisms. Furthermore, the toxicity of IONPs alone and constituting nanosystems is also addressed. Full article
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Open AccessReview Actinomycetes, an Inexhaustible Source of Naturally Occurring Antibiotics
Antibiotics 2018, 7(2), 45; https://doi.org/10.3390/antibiotics7020045
Received: 17 April 2018 / Revised: 7 May 2018 / Accepted: 23 May 2018 / Published: 24 May 2018
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Abstract
Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute
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Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute has been in the vanguard of many such advances, and work is being proactively tailored to promote the discovery of urgently needed antimicrobials. Efforts are being concentrated on actinomycetes, the proven source of most modern antibiotics. We devised a novel physicochemical screening mechanism, whereby simple physico-chemical properties, in conjunction with related detection methods, such as LC/MS, LC/UV, and polarity, could be used to identify or predict new compounds in a culture broth, simply by comparing results with existing databases. New compounds are isolated, purified, and their structure determined before being tested for any bioactivity. We used lyophilized actinomycete strains from the Kitasato Microbial Library, most more than 35 years old, and found 330 strains were producers of useful bioactive substances. We also tested organisms found in fresh samples collected in the complex environments from around plant roots, as well as from sediments of mangrove forests and oceans, resulting in the discovery of 36 novel compounds from 11 actinomycete strains. A compound, designated iminimycin, containing an iminium ion in the structure was discovered from the culture broth of Streptomyces griseus OS-3601, which had been stored for a long time as a streptomycin-producing strain. This represented the first iminium ion discovery in actinomycetes. Compounds with a cyclopentadecane skeleton containing 5,6-dihydro-4-hydroxyl-2-pyrone ring and tetrahydrofuran ring, designated mangromicins, were isolated from the culture broth of Lechevalieria aerocolonigenes K10-0216 obtained from sediment in a mangrove forest. These structures are extremely unique among natural compounds. From the same culture broth, new steroid compounds, named K10-0216 KA and KB, and other new compounds having a thiazole and a pyridine ring, named pyrizomicin A and B, were discovered. New substances can be found from actinomycetes that have been exhaustively studied. Novel compounds with different skeletons can be found from a single broth of one strain. The sought after new antibiotics will arise from continued exploitation of the actinomycetes, especially rare actinomycetes. Work on new organisms and samples should be augmented by re-examination of known actinomycetes already in storage. New research should also be carried out on the manipulation of culture media, thereby stimulating actinomycete strains to produce novel chemicals. The establishment of wide-ranging international research collaborations will facilitate and expedite the efficient and timely discovery and provision of bioactive compounds to help maintain and promote advances in global public health. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Concepts and Methods to Access Novel Antibiotics from Actinomycetes
Antibiotics 2018, 7(2), 44; https://doi.org/10.3390/antibiotics7020044
Received: 12 April 2018 / Revised: 14 May 2018 / Accepted: 17 May 2018 / Published: 22 May 2018
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Abstract
Actinomycetes have been proven to be an excellent source of secondary metabolites for more than half a century. Exhibiting various bioactivities, they provide valuable approved drugs in clinical use. Most microorganisms are still untapped in terms of their capacity to produce secondary metabolites,
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Actinomycetes have been proven to be an excellent source of secondary metabolites for more than half a century. Exhibiting various bioactivities, they provide valuable approved drugs in clinical use. Most microorganisms are still untapped in terms of their capacity to produce secondary metabolites, since only a small fraction can be cultured in the laboratory. Thus, improving cultivation techniques to extend the range of secondary metabolite producers accessible under laboratory conditions is an important first step in prospecting underexplored sources for the isolation of novel antibiotics. Currently uncultured actinobacteria can be made available by bioprospecting extreme or simply habitats other than soil. Furthermore, bioinformatic analysis of genomes reveals most producers to harbour many more biosynthetic gene clusters than compounds identified from any single strain, which translates into a silent biosynthetic potential of the microbial world for the production of yet unknown natural products. This review covers discovery strategies and innovative methods recently employed to access the untapped reservoir of natural products. The focus is the order of actinomycetes although most approaches are similarly applicable to other microbes. Advanced cultivation methods, genomics- and metagenomics-based approaches, as well as modern metabolomics-inspired methods are highlighted to emphasise the interplay of different disciplines to improve access to novel natural products. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Reevaluation of the Acute Cystitis Symptom Score, a Self-Reporting Questionnaire. Part II. Patient-Reported Outcome Assessment
Antibiotics 2018, 7(2), 43; https://doi.org/10.3390/antibiotics7020043
Received: 15 April 2018 / Revised: 12 May 2018 / Accepted: 16 May 2018 / Published: 21 May 2018
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Abstract
This study aimed to reevaluate the Acute Cystitis Symptom Score (ACSS). The ACSS is a self-reporting questionnaire for the clinical diagnosis of acute uncomplicated cystitis (AC) and the assessment of symptomatic changes after therapy in female patients with AC. The part II of
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This study aimed to reevaluate the Acute Cystitis Symptom Score (ACSS). The ACSS is a self-reporting questionnaire for the clinical diagnosis of acute uncomplicated cystitis (AC) and the assessment of symptomatic changes after therapy in female patients with AC. The part II of the present study was to reevaluate the utility of the different domains of the ACSS after therapy. The applicability of these domains in assessing changes in symptoms, as a function of time, in this population was investigated. The ACSS was evaluated in 48 female patients (mean age 31.1 ± 10.6) in the Uzbek and Russian languages, who returned after therapy and filled in part B of the ACSS, which corresponds to part A with the additional “Dynamics” domain. Descriptive statistics were used, where suitable. The reduction of typical symptoms and quality of life assessment between first and follow-up visit correlated significantly with answers in the “Dynamics” domain. Success/Cure and Non-success/Failure could be clearly differentiated by the scores obtained in “Typical” and “Quality of Life” domains. The ACSS has proven to be a useful instrument to clinically diagnose AC in women. It is also a suitable instrument for patient-reported outcome measures, with applicability both in daily practice and clinical studies. Slight modifications in the “Dynamics” domain will even increase the applicability. Full article
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Open AccessArticle Exploring the Effect of Phage Therapy in Preventing Vibrio anguillarum Infections in Cod and Turbot Larvae
Antibiotics 2018, 7(2), 42; https://doi.org/10.3390/antibiotics7020042
Received: 30 December 2017 / Revised: 1 May 2018 / Accepted: 10 May 2018 / Published: 16 May 2018
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Abstract
The aquaculture industry is suffering from losses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important pathogens, causing vibriosis in fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics and inefficient
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The aquaculture industry is suffering from losses associated with bacterial infections by opportunistic pathogens. Vibrio anguillarum is one of the most important pathogens, causing vibriosis in fish and shellfish cultures leading to high mortalities and economic losses. Bacterial resistance to antibiotics and inefficient vaccination at the larval stage of fish emphasizes the need for novel approaches, and phage therapy for controlling Vibrio pathogens has gained interest in the past few years. In this study, we examined the potential of the broad-host-range phage KVP40 to control four different V. anguillarum strains in Atlantic cod (Gadus morhua L.) and turbot (Scophthalmus maximus L.) larvae. We examined larval mortality and abundance of bacteria and phages. Phage KVP40 was able to reduce and/or delay the mortality of the cod and turbot larvae challenged with V. anguillarum. However, growth of other pathogenic bacteria naturally occurring on the fish eggs prior to our experiment caused mortality of the larvae in the unchallenged control groups. Interestingly, the broad-spectrum phage KVP40 was able to reduce mortality in these groups, compared to the nonchallenge control groups not treated with phage KVP40, demonstrating that the phage could also reduce mortality imposed by the background population of pathogens. Overall, phage-mediated reduction in mortality of cod and turbot larvae in experimental challenge assays with V. anguillarum pathogens suggested that application of broad-host-range phages can reduce Vibrio-induced mortality in turbot and cod larvae, emphasizing that phage therapy is a promising alternative to traditional treatment of vibriosis in marine aquaculture. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessReview Streptomyces Differentiation in Liquid Cultures as a Trigger of Secondary Metabolism
Antibiotics 2018, 7(2), 41; https://doi.org/10.3390/antibiotics7020041
Received: 26 February 2018 / Revised: 9 May 2018 / Accepted: 9 May 2018 / Published: 14 May 2018
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Abstract
Streptomyces is a diverse group of gram-positive microorganisms characterised by a complex developmental cycle. Streptomycetes produce a number of antibiotics and other bioactive compounds used in the clinic. Most screening campaigns looking for new bioactive molecules from actinomycetes have been performed empirically, e.g.,
[...] Read more.
Streptomyces is a diverse group of gram-positive microorganisms characterised by a complex developmental cycle. Streptomycetes produce a number of antibiotics and other bioactive compounds used in the clinic. Most screening campaigns looking for new bioactive molecules from actinomycetes have been performed empirically, e.g., without considering whether the bacteria are growing under the best developmental conditions for secondary metabolite production. These screening campaigns were extremely productive and discovered a number of new bioactive compounds during the so-called “golden age of antibiotics” (until the 1980s). However, at present, there is a worrying bottleneck in drug discovery, and new experimental approaches are needed to improve the screening of natural actinomycetes. Streptomycetes are still the most important natural source of antibiotics and other bioactive compounds. They harbour many cryptic secondary metabolite pathways not expressed under classical laboratory cultures. Here, we review the new strategies that are being explored to overcome current challenges in drug discovery. In particular, we focus on those aimed at improving the differentiation of the antibiotic-producing mycelium stage in the laboratory. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle Toxicological Assessment of a Lignin Core Nanoparticle Doped with Silver as an Alternative to Conventional Silver Core Nanoparticles
Antibiotics 2018, 7(2), 40; https://doi.org/10.3390/antibiotics7020040
Received: 29 March 2018 / Revised: 27 April 2018 / Accepted: 2 May 2018 / Published: 4 May 2018
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Abstract
Elevated levels of silver in the environment are anticipated with an increase in silver nanoparticle (AgNP) production and use in consumer products. To potentially reduce the burden of silver ion release from conventional solid core AgNPs, a lignin-core particle doped with silver ions
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Elevated levels of silver in the environment are anticipated with an increase in silver nanoparticle (AgNP) production and use in consumer products. To potentially reduce the burden of silver ion release from conventional solid core AgNPs, a lignin-core particle doped with silver ions and surface-stabilized with a polycationic electrolyte layer was engineered. Our objective was to determine whether any of the formulation components elicit toxicological responses using embryonic zebrafish. Ionic silver and free surface stabilizer were the most toxic constituents, although when associated separately or together with the lignin core particles, the toxicity of the formulations decreased significantly. The overall toxicity of lignin formulations containing silver was similar to other studies on a silver mass basis, and led to a significantly higher prevalence of uninflated swim bladder and yolk sac edema. Comparative analysis of dialyzed samples which had leached their loosely bound Ag+, showed a significant increase in mortality immediately after dialysis, in addition to eliciting significant increases in types of sublethal responses relative to the freshly prepared non-dialyzed samples. ICP-OES/MS analysis indicated that silver ion release from the particle into solution was continuous, and the rate of release differed when the surface stabilizer was not present. Overall, our study indicates that the lignin core is an effective alternative to conventional solid core AgNPs for potentially reducing the burden of silver released into the environment from a variety of consumer products. Full article
(This article belongs to the Special Issue Silver-Based Antimicrobials)
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Open AccessReview Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in Streptomyces tsukubaensis through omic Approaches
Antibiotics 2018, 7(2), 39; https://doi.org/10.3390/antibiotics7020039
Received: 27 February 2018 / Revised: 23 April 2018 / Accepted: 26 April 2018 / Published: 1 May 2018
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Abstract
Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been
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Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been proposed in the last years. In this review we introduce the discovery of S. tsukubaensis and tacrolimus, its biosynthetic pathway and gene cluster (fkb) regulation. We have focused this work on the omic studies performed in this species in order to understand tacrolimus production. Transcriptomics, proteomics and metabolomics have improved our knowledge about the fkb transcriptional regulation and have given important clues about nutritional regulation of tacrolimus production that can be applied to improve production yields. Finally, we address some points of S. tsukubaensis biology that deserve more attention. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Antibiotic Prescribing for Oro-Facial Infections in the Paediatric Outpatient: A Review
Antibiotics 2018, 7(2), 38; https://doi.org/10.3390/antibiotics7020038
Received: 15 February 2018 / Revised: 18 April 2018 / Accepted: 24 April 2018 / Published: 25 April 2018
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Abstract
There are many reports on the complications associated with antibiotics abuse during the treatment of paediatric patients, particularly those related to antimicrobial resistance. The dental profession is no exception; there is growing evidence that dental practitioners are misusing antibiotics in the treatment of
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There are many reports on the complications associated with antibiotics abuse during the treatment of paediatric patients, particularly those related to antimicrobial resistance. The dental profession is no exception; there is growing evidence that dental practitioners are misusing antibiotics in the treatment of their paediatric patients. This review is directed to dental practitioners who provide oral healthcare to children. It is also directed to medical practitioners, particularly those working in emergency departments and encountering children with acute orofacial infections. A systematic search of literature was conducted to explore the clinical indications and recommended antibiotic regimens for orofacial infections in paediatric outpatients. The main indications included cellulitis, aggressive periodontitis, necrotizing ulcerative gingivitis, and pericoronitis. Amoxicillin was found to be the most commonly recommended antibiotic for short durations of 3–5 days, with metronidazole or azithromycin being the alternative antibiotics in penicillin-sensitive patients. Full article
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Open AccessArticle Comparison of Staphylococcus Phage K with Close Phage Relatives Commonly Employed in Phage Therapeutics
Antibiotics 2018, 7(2), 37; https://doi.org/10.3390/antibiotics7020037
Received: 9 March 2018 / Revised: 12 April 2018 / Accepted: 19 April 2018 / Published: 25 April 2018
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Abstract
The increase in antibiotic resistance in pathogenic bacteria is a public health danger requiring alternative treatment options, and this has led to renewed interest in phage therapy. In this respect, we describe the distinct host ranges of Staphylococcus phage K, and two other
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The increase in antibiotic resistance in pathogenic bacteria is a public health danger requiring alternative treatment options, and this has led to renewed interest in phage therapy. In this respect, we describe the distinct host ranges of Staphylococcus phage K, and two other K-like phages against 23 isolates, including 21 methicillin-resistant S. aureus (MRSA) representative sequence types representing the Irish National MRSA Reference Laboratory collection. The two K-like phages were isolated from the Fersisi therapeutic phage mix from the Tbilisi Eliava Institute, and were designated B1 (vB_SauM_B1) and JA1 (vB_SauM_JA1). The sequence relatedness of B1 and JA1 to phage K was observed to be 95% and 94% respectively. In terms of host range on the 23 Staphylococcus isolates, B1 and JA1 infected 73.9% and 78.2% respectively, whereas K infected only 43.5%. Eleven open reading frames (ORFs) present in both phages B1 and JA1 but absent in phage K were identified by comparative genomic analysis. These ORFs were also found to be present in the genomes of phages (Team 1, vB_SauM-fRuSau02, Sb_1 and ISP) that are components of several commercial phage mixtures with reported wide host ranges. This is the first comparative study of therapeutic staphylococcal phages within the recently described genus Kayvirus. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Specificity of Induction of Glycopeptide Antibiotic Resistance in the Producing Actinomycetes
Antibiotics 2018, 7(2), 36; https://doi.org/10.3390/antibiotics7020036
Received: 28 February 2018 / Revised: 19 April 2018 / Accepted: 20 April 2018 / Published: 25 April 2018
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Abstract
Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by Gram-positive pathogens. It is widely believed that glycopeptide-resistance determinants (van genes) are ultimately derived from the producing actinomycetes. We hereby investigated the relationship between the antimicrobial activity of vancomycin
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Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by Gram-positive pathogens. It is widely believed that glycopeptide-resistance determinants (van genes) are ultimately derived from the producing actinomycetes. We hereby investigated the relationship between the antimicrobial activity of vancomycin and teicoplanins and their differential ability to induce van gene expression in Actinoplanes teichomyceticus—the producer of teicoplanin—and Nonomuraea gerenzanensis—the producer of the teicoplanin-like A40926. As a control, we used the well-characterized resistance model Streptomyces coelicolor. The enzyme activities of a cytoplasmic-soluble d,d-dipeptidase and of a membrane-associated d,d-carboxypeptidase (corresponding to VanX and VanY respectively) involved in resistant cell wall remodeling were measured in the actinomycetes grown in the presence or absence of subinhibitory concentrations of vancomycin, teicoplanin, and A40926. Results indicated that actinomycetes possess diverse self-resistance mechanisms, and that each of them responds differently to glycopeptide induction. Gene swapping among teicoplanins-producing actinomycetes indicated that cross-talking is possible and provides useful information for predicting the evolution of future resistance gene combinations emerging in pathogens. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessPerspective Silk Route to the Acceptance and Re-Implementation of Bacteriophage Therapy—Part II
Antibiotics 2018, 7(2), 35; https://doi.org/10.3390/antibiotics7020035
Received: 25 March 2018 / Revised: 12 April 2018 / Accepted: 12 April 2018 / Published: 23 April 2018
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Abstract
This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a
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This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a society that is confronted with an ever-increasing number of antibiotic-resistant bacteria, we build on the previously made recommendations and specifically address how the Nagoya Protocol might impact the further development of bacteriophage therapy. By reviewing a number of recently conducted case studies with bacteriophages involving patients with bacterial infections that could no longer be successfully treated by regular antibiotic therapy, we again stress the urgency and significance of the development of international guidelines and frameworks that might facilitate the legal and effective application of bacteriophage therapy by physicians and the receiving patients. Additionally, we list and comment on several recently started and ongoing clinical studies, including highly desired double-blind placebo-controlled randomized clinical trials. We conclude with an outlook on how recently developed DNA editing technologies are expected to further control and enhance the efficient application of bacteriophages. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
Open AccessArticle Veterinary Students’ Knowledge and Perceptions About Antimicrobial Stewardship and Biosecurity—A National Survey
Antibiotics 2018, 7(2), 34; https://doi.org/10.3390/antibiotics7020034
Received: 9 March 2018 / Revised: 16 April 2018 / Accepted: 17 April 2018 / Published: 18 April 2018
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Abstract
A better understanding of veterinary students’ perceptions, attitudes, and knowledge about antimicrobial stewardship and biosecurity could facilitate more effective education of future veterinarians about these important issues. A multicenter cross-sectional study was performed by administering a questionnaire to veterinary students expected to graduate
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A better understanding of veterinary students’ perceptions, attitudes, and knowledge about antimicrobial stewardship and biosecurity could facilitate more effective education of future veterinarians about these important issues. A multicenter cross-sectional study was performed by administering a questionnaire to veterinary students expected to graduate in 2017 or 2018 in all Australian veterinary schools. Four hundred and seventy-six of 1246 students (38%) completed the survey. Many students were unaware of the high importance of some veterinary drugs to human medicine, specifically enrofloxacin and cefovecin (59% and 47% of responses, respectively). Fewer than 10% of students would use appropriate personal protective equipment in scenarios suggestive of Q fever or psittacosis. Students expected to graduate in 2018 were more likely to select culture and susceptibility testing in companion animal cases (OR 1.89, 95% CI 1.33–2.69, p < 0.001), and were more likely to appropriately avoid antimicrobials in large animal cases (OR 1.75, 95% CI 1.26–2.44, p = 0.001) than those expected to graduate in 2017. However, 2018 graduates were less likely to correctly identify the importance rating of veterinary antimicrobials for human health (OR 0.48, 95% CI 0.34–0.67, p < 0.001) than 2017 graduates. Students reported having a good knowledge of antimicrobial resistance, and combating resistance, but only 34% thought pharmacology teaching was adequate and only 20% said that teaching in lectures matched clinical teaching. Efforts need to be made to harmonize preclinical and clinical teaching, and greater emphasis is needed on appropriate biosecurity and antimicrobial stewardship. Full article
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Open AccessFeature PaperReview The Cellular Mechanisms that Ensure an Efficient Secretion in Streptomyces
Antibiotics 2018, 7(2), 33; https://doi.org/10.3390/antibiotics7020033
Received: 27 February 2018 / Revised: 10 April 2018 / Accepted: 11 April 2018 / Published: 14 April 2018
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Abstract
Gram-positive soil bacteria included in the genus Streptomyces produce a large variety of secondary metabolites in addition to extracellular hydrolytic enzymes. From the industrial and commercial viewpoints, the S. lividans strain has generated greater interest as a host bacterium for the overproduction of
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Gram-positive soil bacteria included in the genus Streptomyces produce a large variety of secondary metabolites in addition to extracellular hydrolytic enzymes. From the industrial and commercial viewpoints, the S. lividans strain has generated greater interest as a host bacterium for the overproduction of homologous and heterologous hydrolytic enzymes as an industrial application, which has considerably increased scientific interest in the characterization of secretion routes in this bacterium. This review will focus on the secretion machinery in S. lividans. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Our Evolving Understanding of the Mechanism of Quinolones
Antibiotics 2018, 7(2), 32; https://doi.org/10.3390/antibiotics7020032
Received: 9 February 2018 / Revised: 30 March 2018 / Accepted: 4 April 2018 / Published: 8 April 2018
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Abstract
The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double
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The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double helix. Resolution of DNA supercoiling is essential to maintain DNA replication rates that are amenable to life. This resolution is handled by evolutionarily conserved enzymes known as topoisomerases. The activity of topoisomerases is essential, and therefore constitutes a prime candidate for targeting by antibiotics. In this review, we present hallmark investigations describing the mode of action of quinolones, one of the antibacterial classes targeting the function of topoisomerases in bacteria. By chronologically analyzing data gathered on the mode of action of this imperative antibiotic class, we highlight the necessity to look beyond primary drug-target interactions towards thoroughly understanding the mechanism of quinolones at the level of the cell. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
Open AccessArticle Complementation Studies of Bacteriophage λ O Amber Mutants by Allelic Forms of O Expressed from Plasmid, and O-P Interaction Phenotypes
Antibiotics 2018, 7(2), 31; https://doi.org/10.3390/antibiotics7020031
Received: 27 February 2018 / Revised: 25 March 2018 / Accepted: 3 April 2018 / Published: 5 April 2018
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Abstract
λ genes O and P are required for replication initiation from the bacteriophage λ origin site, oriλ, located within gene O. Questions have persisted for years about whether O-defects can indeed be complemented in trans. We show the effect of
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λ genes O and P are required for replication initiation from the bacteriophage λ origin site, oriλ, located within gene O. Questions have persisted for years about whether O-defects can indeed be complemented in trans. We show the effect of original null mutations in O and the influence of four origin mutations (three are in-frame deletions and one is a point mutation) on complementation. This is the first demonstration that O proteins with internal deletions can complement for O activity, and that expression of the N-terminal portion of gene P can completely prevent O complementation. We show that O-P co-expression can limit the lethal effect of P on cell growth. We explore the influence of the contiguous small RNA OOP on O complementation and P-lethality. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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Open AccessReview Complex Regulatory Networks Governing Production of the Glycopeptide A40926
Antibiotics 2018, 7(2), 30; https://doi.org/10.3390/antibiotics7020030
Received: 9 March 2018 / Revised: 29 March 2018 / Accepted: 3 April 2018 / Published: 5 April 2018
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Abstract
Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached
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Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis. This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoBR, have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessReview Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials
Antibiotics 2018, 7(2), 29; https://doi.org/10.3390/antibiotics7020029
Received: 2 February 2018 / Revised: 16 March 2018 / Accepted: 20 March 2018 / Published: 22 March 2018
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Abstract
Lytic enzymes encoded by bacteriophages have been intensively explored as alternative agents for combating bacterial pathogens in different contexts. The antibacterial character of these enzymes (enzybiotics) results from their degrading activity towards peptidoglycan, an essential component of the bacterial cell wall. In fact,
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Lytic enzymes encoded by bacteriophages have been intensively explored as alternative agents for combating bacterial pathogens in different contexts. The antibacterial character of these enzymes (enzybiotics) results from their degrading activity towards peptidoglycan, an essential component of the bacterial cell wall. In fact, phage lytic products have the capacity to kill target bacteria when added exogenously in the form of recombinant proteins. However, there is also growing recognition that the natural bactericidal activity of these agents can, and sometimes needs to be, substantially improved through manipulation of their functional domains or by equipping them with new functions. In addition, often, native lytic proteins exhibit features that restrict their applicability as effective antibacterials, such as poor solubility or reduced stability. Here, I present an overview of the engineering approaches that can be followed not only to overcome these and other restrictions, but also to generate completely new antibacterial agents with significantly enhanced characteristics. As conventional antibiotics are running short, the remarkable progress in this field opens up the possibility of tailoring efficient enzybiotics to tackle the most menacing bacterial infections. Full article
(This article belongs to the Special Issue Bacteriophages: Alternatives to Antibiotics and Beyond)
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Open AccessArticle Isolation, Characterization, and Antibacterial Activity of Hard-to-Culture Actinobacteria from Cave Moonmilk Deposits
Antibiotics 2018, 7(2), 28; https://doi.org/10.3390/antibiotics7020028
Received: 26 February 2018 / Revised: 16 March 2018 / Accepted: 19 March 2018 / Published: 22 March 2018
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Abstract
Cave moonmilk deposits host an abundant and diverse actinobacterial population that has a great potential for producing novel natural bioactive compounds. In our previous attempt to isolate culturable moonmilk-dwelling Actinobacteria, only Streptomyces species were recovered, whereas a metagenetic study of the same deposits
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Cave moonmilk deposits host an abundant and diverse actinobacterial population that has a great potential for producing novel natural bioactive compounds. In our previous attempt to isolate culturable moonmilk-dwelling Actinobacteria, only Streptomyces species were recovered, whereas a metagenetic study of the same deposits revealed a complex actinobacterial community including 46 actinobacterial genera in addition to streptomycetes. In this work, we applied the rehydration-centrifugation method to lessen the occurrence of filamentous species and tested a series of strategies to achieve the isolation of hard-to-culture and rare Actinobacteria from the moonmilk deposits of the cave “Grotte des Collemboles”. From the “tips and tricks” that were tested, separate autoclaving of the components of the International Streptomyces Project (ISP) medium number 5 (ISP5) medium, prolonged incubation time, and dilution of the moonmilk suspension were found to most effectively improve colony forming units. Taxonomic analyses of the 40 isolates revealed new representatives of the Agromyces, Amycolatopsis, Kocuria, Micrococcus, Micromonospora, Nocardia, and Rhodococcus species, as well as additional new streptomycetes. The applied methodologies allowed the isolation of strains associated with both the least and most abundant moonmilk-dwelling actinobacterial operational taxonomic units. Finally, bioactivity screenings revealed that some isolates displayed high antibacterial activities, and genome mining uncovered a strong potential for the production of natural compounds. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Open AccessArticle High-Throughput Sequencing Analysis of the Actinobacterial Spatial Diversity in Moonmilk Deposits
Antibiotics 2018, 7(2), 27; https://doi.org/10.3390/antibiotics7020027
Received: 12 February 2018 / Revised: 15 March 2018 / Accepted: 16 March 2018 / Published: 21 March 2018
Cited by 1 | PDF Full-text (1727 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Moonmilk are cave carbonate deposits that host a rich microbiome, including antibiotic-producing Actinobacteria, making these speleothems appealing for bioprospecting. Here, we investigated the taxonomic profile of the actinobacterial community of three moonmilk deposits of the cave “Grotte des Collemboles” via high-throughput sequencing of
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Moonmilk are cave carbonate deposits that host a rich microbiome, including antibiotic-producing Actinobacteria, making these speleothems appealing for bioprospecting. Here, we investigated the taxonomic profile of the actinobacterial community of three moonmilk deposits of the cave “Grotte des Collemboles” via high-throughput sequencing of 16S rRNA amplicons. Actinobacteria was the most common phylum after Proteobacteria, ranging from 9% to 23% of the total bacterial population. Next to actinobacterial operational taxonomic units (OTUs) attributed to uncultured organisms at the genus level (~44%), we identified 47 actinobacterial genera with Rhodoccocus (4 OTUs, 17%) and Pseudonocardia (9 OTUs, ~16%) as the most abundant in terms of the absolute number of sequences. Streptomycetes presented the highest diversity (19 OTUs, 3%), with most of the OTUs unlinked to the culturable Streptomyces strains that were previously isolated from the same deposits. Furthermore, 43% of the OTUs were shared between the three studied collection points, while 34% were exclusive to one deposit, indicating that distinct speleothems host their own population, despite their nearby localization. This important spatial diversity suggests that prospecting within different moonmilk deposits should result in the isolation of unique and novel Actinobacteria. These speleothems also host a wide range of non-streptomycetes antibiotic-producing genera, and should therefore be subjected to methodologies for isolating rare Actinobacteria. Full article
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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