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Pharmaceutics
Special Issues
Recent Trends in Antibiotic Drug Development
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Recent Trends in Antibiotic Drug Development

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 13721

Special Issue Editor

Dr. Tihomir Tomašič

E-Mail Website
Guest Editor
Faculty of Pharmacy, University of Ljubljana, Kongresni trg 12, 1000 Ljubljana, Slovenia
Interests: drug design; medicinal chemistry; molecular modelling; antibacterial agents; anticancer agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The increasing number of life-threatening infections due to resistant Gram-positive and Gram-negative pathogens is becoming more and more alarming. In the last 50 years, only a small number of new chemical classes of antibacterial agents have reached clinical practice, while at the same time, the number of multi-drug-resistant bacteria is rising. In 2017 the World Health Organisation published a list of bacteria for which new antibiotics are urgently needed. Among these, Gram-negative carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae have the highest, critical level of priority, followed by the Gram-positive Staphylococcus aureus and Enterococcus faecium resistant strains. New antibacterial drugs with novel mechanisms of action and novel strategies are thus needed to successfully fight these pathogens in the future.

The focus of this Special Issue in Pharmaceutics will be devoted to recent advances in the development of small molecules as well as alternative strategies for treating infections with Gram-positive and Gram-negative bacteria.

Dr. Tihomir Tomašič
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibiotic resistance
  • bacterial enzymes as drug targets
  • compounds targeting bacterial DNA and RNA biosynthesis
  • compounds targeting peptidoglycan biosynthesis
  • efflux pumps and porins
  • siderophores
  • quorum sensing
  • bacterial biofilms
  • rules for permeation and accumulation in bacteria

Published Papers (4 papers)

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Research

21 pages, 1897 KiB  
Article
The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions—Synthesis and Antibacterial Studies
by Son Thai Le, Dávid Páll, Erzsébet Rőth, Tuyen Tran, Nóra Debreczeni, Miklós Bege, Ilona Bereczki, Eszter Ostorházi, Márton Milánkovits, Pál Herczegh, Anikó Borbás and Magdolna Csávás
Pharmaceutics 2021, 13(12), 2028; https://doi.org/10.3390/pharmaceutics13122028 - 28 Nov 2021
Cited by 5 | Viewed by 2555
Abstract
Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a [...] Read more.
Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19–C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties. Full article
(This article belongs to the Special Issue Recent Trends in Antibiotic Drug Development)
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15 pages, 3487 KiB  
Article
Synergistic In Vitro Antimicrobial Activity of Pomegranate Rind Extract and Zinc (II) against Micrococcus luteus under Planktonic and Biofilm Conditions
by Vildan Celiksoy, Rachael L. Moses, Alastair J. Sloan, Ryan Moseley and Charles M. Heard
Pharmaceutics 2021, 13(6), 851; https://doi.org/10.3390/pharmaceutics13060851 - 8 Jun 2021
Cited by 11 | Viewed by 3608
Abstract
Infectious diseases caused by microbial biofilms are a major clinical problem, and new antimicrobial agents that can inhibit biofilm formation and eradicate pre-formed biofilms are urgently needed. Pomegranate extracts are a well-established folkloric medicine and have been used in the treatment of infectious [...] Read more.
Infectious diseases caused by microbial biofilms are a major clinical problem, and new antimicrobial agents that can inhibit biofilm formation and eradicate pre-formed biofilms are urgently needed. Pomegranate extracts are a well-established folkloric medicine and have been used in the treatment of infectious diseases since ancient times, whilst the addition of metal ions, including zinc (II), has enhanced the antimicrobial activity of pomegranate. Micrococcus luteus is generally a non-pathogenic skin commensal bacterium, although it can act as an opportunistic pathogen and cause serious infections, particularly involving catheterization and comorbidities. The aims of this study were to evaluate the holistic activity of pomegranate rind extract (PRE), Zn (II), and PRE/Zn (II) individually and in combination against M. luteus under both planktonic and biofilm conditions. Antimicrobial activity was detected in vitro using the broth dilution method, and synergistic activity was determined using checkerboard and time-kill assays. Effects on biofilm formation and eradication were determined by crystal violet and BacLightTM Live/Dead staining. PRE and Zn (II) exerted antimicrobial activity against M. luteus under both planktonic and biofilm conditions. After 4 h, potent synergistic bactericidal activity was also found when PRE and Zn (II) were co-administered under planktonic conditions (log reductions: PRE 1.83 ± 0.24, Zn (II) 3.4 ± 0.08, and PRE/Zn (II) 6.88 ± 1.02; p < 0.0001). In addition, greater heterogeneity was induced in the structure of M. luteus biofilm using the PRE/Zn (II) combination compared to when PRE and Zn (II) were applied individually. The activity of PRE and the PRE/Zn (II) combination could offer a novel antimicrobial therapy for the treatment of disease-associated infections caused by M. luteus and potentially other bacteria. Full article
(This article belongs to the Special Issue Recent Trends in Antibiotic Drug Development)
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15 pages, 3004 KiB  
Article
Activation of Deoxyribonuclease I by Nicotinamide as a New Strategy to Attenuate Tetracycline-Resistant Biofilms of Cutibacterium acnes
by Yi-Hsien Shih, Donald Liu, Yen-Chou Chen, Ming-Hsuan Liao, Woan-Ruoh Lee and Shing-Chuan Shen
Pharmaceutics 2021, 13(6), 819; https://doi.org/10.3390/pharmaceutics13060819 - 31 May 2021
Cited by 7 | Viewed by 2762
Abstract
Biofilms of Cutibacterium (C.) acnes (formerly Propionibacterium acnes) are responsible for the persistence and antibiotic resistance of acne vulgaris. In addition to the standard treatments for acne vulgaris, a common adjunctive treatment is the topical administration of nicotinamide (NAM). However, [...] Read more.
Biofilms of Cutibacterium (C.) acnes (formerly Propionibacterium acnes) are responsible for the persistence and antibiotic resistance of acne vulgaris. In addition to the standard treatments for acne vulgaris, a common adjunctive treatment is the topical administration of nicotinamide (NAM). However, the effects of NAM on biofilms of C. acnes have never been explored. This study comprehensively investigates the effects of NAM against biofilms of C. acnes using in vitro and in vivo approaches. The results showed that NAM potentiated the efficacy of suboptimal dosing of tetracycline against C. acnes. Moreover, NAM alone decreased the formation and increased the degradation of biofilms in C. acnes. The antibiofilm effect of NAM against C. acnes was further enhanced in combination with deoxyribonuclease (DNase) I, an enzyme with known antibiofilm properties. The computational molecular docking, surface plasmon resonance analysis, and enzymatic kinetic assay demonstrated that NAM binds to DNase I and accelerated its reaction. In conclusion, NAM activates DNase I to attenuate biofilms of C. acnes. This offers valuable insights into the strategies against biofilms that are worth elaborating on in other biofilm-related chronic cutaneous infections in the future. Full article
(This article belongs to the Special Issue Recent Trends in Antibiotic Drug Development)
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17 pages, 3499 KiB  
Article
Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation
by Martina Durcik, Žiga Skok, Janez Ilaš, Nace Zidar, Anamarija Zega, Petra Éva Szili, Gábor Draskovits, Tamás Révész, Danijel Kikelj, Akos Nyerges, Csaba Pál, Lucija Peterlin Mašič and Tihomir Tomašič
Pharmaceutics 2021, 13(1), 6; https://doi.org/10.3390/pharmaceutics13010006 - 22 Dec 2020
Cited by 8 | Viewed by 3690
Abstract
The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their [...] Read more.
The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their ATP binding sites. Here we present the design of new hybrids between the catalytic inhibitor ciprofloxacin and ATP-competitive inhibitors that show low nanomolar inhibition of DNA gyrase and antibacterial activity against Gram-negative pathogens. The most potent hybrid 3a has MICs of 0.5 µg/mL against Klebsiella pneumoniae, 4 µg/mL against Enterobacter cloacae, and 2 µg/mL against Escherichia coli. In addition, inhibition of mutant E. coli strains shows that these hybrid inhibitors interact with both subunits of DNA gyrase (GyrA, GyrB), and that binding to both of these sites contributes to their antibacterial activity. Full article
(This article belongs to the Special Issue Recent Trends in Antibiotic Drug Development)
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