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Antibiotics
Special Issues
Discovery and Development of Novel Antibacterial Agents
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Discovery and Development of Novel Antibacterial Agents

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (1 September 2022) | Viewed by 20273

Special Issue Editor

Prof. Dr. Kui Zhu

E-Mail Website
Guest Editor
College of Veterinary Medicine, China Agricultural University, Beijing, China
Interests: antibiotic discovery; antibacterial target; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The particularly noteworthy emergence and dissemination of multidrug-resistant bacterial pathogens are one of the biggest ever crises to One Health worldwide. Meanwhile, the depletion of developing pipelines of antibacterial drugs further aggravates the threat created by pathogenic bacteria, leading to almost no new antibiotics introduced to the clinic in the past decade. To accelerate the process of antibiotic discovery, novel antibacterial agents and alternative strategies including new antibiotics, antibiotic adjuvants, antivirulence approaches, probiotics, immune-modulators, and phages are urgently required to address such a global threat.

This Special Issue will focus on the following topics: (1) the discovery of novel antibacterial natural products derived from microbial organisms, plants, etc.; (2) the identification and conformation of potential antibacterial targets particularly in Gram-negative bacteria; (3) a deep mechanistic understanding of the diverse ways for revitalizing existing antibiotics, to shed light on developing rational medication; (4) the emerging approach of host-directed therapy attracts increasing attentions recently by modulating either host immune responses or colonization resistance, to eliminate or diminish infections associated with multidrug-resistant bacterial pathogens.

Prof. Dr. Kui Zhu
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. Antibiotics 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
  • antibiotic adjuvant
  • natural product
  • probiotic
  • target

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Related Special Issue

Published Papers (7 papers)

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Research

16 pages, 2786 KiB  
Article
In Vitro Antimicrobial Effects and Inactivation Mechanisms of 5,8-Dihydroxy-1,4-Napthoquinone
by Seray Topçu and Mine Gül Şeker
Antibiotics 2022, 11(11), 1537; https://doi.org/10.3390/antibiotics11111537 - 3 Nov 2022
Cited by 8 | Viewed by 2385
Abstract
Naphthoquinones are an important class of natural organic compounds that have antimicrobial effects. However, the mechanisms of their action remain to be elucidated. Therefore, the antimicrobial activity of the chemically synthesized naphthoquinone derivative, 5,8-dihydroxy-1,4-naphthoquinone, was investigated in this study against 10 different microorganisms. [...] Read more.
Naphthoquinones are an important class of natural organic compounds that have antimicrobial effects. However, the mechanisms of their action remain to be elucidated. Therefore, the antimicrobial activity of the chemically synthesized naphthoquinone derivative, 5,8-dihydroxy-1,4-naphthoquinone, was investigated in this study against 10 different microorganisms. Its inhibitory activity was evident against Bacillus cereus, Proteus vulgaris, Salmonella enteritidis, Staphylococcus epidermidis, S. aureus, and Candida albicans, and its MIC50 values were determined to be 14, 10, 6, 2, 4, 1.2, and <0.6 µg/mL, respectively. Moreover, the crystal violet uptake, TTC dehydrogenase activity, protein/DNA leakage, and DNA damage of the compound in these microorganisms were also investigated to reveal the antimicrobial mechanisms. In addition, scanning electron microscopy was used to detect physiological damage to the cell membrane of S. epidermidis, S. aureus, and C. albicans, which was most severe in the crystal violet uptake assay. The overall results showed that 5,8-dihydroxy-1,4-naphthoquinone exhibited its effects on S. aureus, S. epidermidis, and C. albicans by various mechanisms, especially membrane damage and membrane integrity disruption. It also caused DNA leakage and damage along with respiratory chain disruption (78%) in C. albicans. Similarly, it caused varying degrees of reduction in the respiratory activity of S. aureus (47%), S. epidermidis (16%), B. cereus (12%), S. enteritidis (9%), and P. vulgaris (8%). Therefore, 5,8-dihydroxy-1,4-naphthoquinone proved to be a very effective antifungal and antibacterial agent and could be considered a new potential drug candidate, inspiring further discoveries in these microorganisms. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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12 pages, 622 KiB  
Article
In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens
by Hongfei Pi, Henrietta Venter, Cecilia C. Russell, Kelly A. Young, Adam McCluskey, Stephen W. Page, Abiodun D. Ogunniyi and Darren J. Trott
Antibiotics 2022, 11(10), 1301; https://doi.org/10.3390/antibiotics11101301 - 23 Sep 2022
Cited by 1 | Viewed by 2033
Abstract
Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine [...] Read more.
Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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17 pages, 3671 KiB  
Article
Mechanism-Based Approach to New Antibiotic Producers Screening among Actinomycetes in the Course of the Citizen Science Project
by Inna A. Volynkina, Yuliya V. Zakalyukina, Vera A. Alferova, Albina R. Belik, Daria K. Yagoda, Arina A. Nikandrova, Yuliya A. Buyuklyan, Andrei V. Udalov, Evgenii V. Golovin, Maxim A. Kryakvin, Dmitrii A. Lukianov, Mikhail V. Biryukov, Petr V. Sergiev, Olga A. Dontsova and Ilya A. Osterman
Antibiotics 2022, 11(9), 1198; https://doi.org/10.3390/antibiotics11091198 - 5 Sep 2022
Cited by 10 | Viewed by 3417
Abstract
Since the discovery of streptomycin, actinomycetes have been a useful source for new antibiotics, but there have been diminishing rates of new finds since the 1960s. The decreasing probability of identifying new active agents led to reduced interest in soil bacteria as a [...] Read more.
Since the discovery of streptomycin, actinomycetes have been a useful source for new antibiotics, but there have been diminishing rates of new finds since the 1960s. The decreasing probability of identifying new active agents led to reduced interest in soil bacteria as a source for new antibiotics. At the same time, actinomycetes remain a promising reservoir for new active molecules. In this work, we present several reporter plasmids encoding visible fluorescent protein genes. These plasmids provide primary information about the action mechanism of antimicrobial agents at an early stage of screening. The reporters and the pipeline described have been optimized and designed to employ citizen scientists without specialized skills or equipment with the aim of essentially crowdsourcing the search for new antibiotic producers in the vast natural reservoir of soil bacteria. The combination of mechanism-based approaches and citizen science has proved its effectiveness in practice, revealing a significant increase in the screening rate. As a proof of concept, two new strains, Streptomyces sp. KB-1 and BV113, were found to produce the antibiotics pikromycin and chartreusin, respectively, demonstrating the efficiency of the pipeline. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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11 pages, 1196 KiB  
Article
Biochemical Characterizations of the Putative Endolysin Ecd09610 Catalytic Domain from Clostridioides difficile
by Hiroshi Sekiya, Hina Yamaji, Ayumi Yoshida, Risa Matsunami, Shigehiro Kamitori and Eiji Tamai
Antibiotics 2022, 11(8), 1131; https://doi.org/10.3390/antibiotics11081131 - 20 Aug 2022
Cited by 3 | Viewed by 2311
Abstract
Clostridioides difficile is the major pathogen of pseudomembranous colitis, and novel antimicrobial agents are sought after for its treatment. Phage-derived endolysins with species-specific lytic activity have potential as novel antimicrobial agents. We surveyed the genome of C. difficile strain 630 and identified an [...] Read more.
Clostridioides difficile is the major pathogen of pseudomembranous colitis, and novel antimicrobial agents are sought after for its treatment. Phage-derived endolysins with species-specific lytic activity have potential as novel antimicrobial agents. We surveyed the genome of C. difficile strain 630 and identified an endolysin gene, Ecd09610, which has an uncharacterized domain at the N-terminus and two catalytic domains that are homologous to glucosaminidase and endopeptidase at the C-terminus. Genes containing the two catalytic domains, the glucosaminidase domain and the endopeptidase domain, were cloned and expressed in Escherichia coli as N-terminal histidine-tagged proteins. The purified domain variants showed lytic activity almost specifically for C. difficile, which has a unique peptide bridge in its peptidoglycan. This species specificity is thought to depend on substrate cleavage activity rather than binding. The domain variants were thermostable, and, notably, the glucosaminidase domain remained active up to 100 °C. In addition, we determined the optimal pH and salt concentrations of these domain variants. Their properties are suitable for formulating a bacteriolytic enzyme as an antimicrobial agent. This lytic enzyme can serve as a scaffold for the construction of high lytic activity mutants with enhanced properties. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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14 pages, 1187 KiB  
Article
Antibacterial Activity against Clinical Isolates and In Vivo Efficacy of Coralmycins
by Ha-Young Choi, Bo-Min Kim, Young-Rok Kim, Taehui Yang, Sunjoo Ahn, Dongeun Yong, Jin-Hwan Kwak and Won-Gon Kim
Antibiotics 2022, 11(7), 902; https://doi.org/10.3390/antibiotics11070902 - 6 Jul 2022
Cited by 3 | Viewed by 2626
Abstract
Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and [...] Read more.
Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and in vivo efficacy of coralmycins were studied. Coralmycin A showed potent antibacterial activity with an MIC90 of 1 mg/L against 73 clinical methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci isolates, which was 2–8 times higher than the corresponding activities of DH-coralmycin A, vancomycin, daptomycin, and linezolid, and against 73 vancomycin-resistant Enterococcus and Streptococcus pneumoniae isolates, which was 4–16 times higher than the corresponding activities of DH-coralmycin A, daptomycin, and linezolid. Pharmacokinetic analysis after i.v. injection showed that coralmycins have a moderate volume of distribution and moderate-to-high clearance in mice. The coralmycin A and DH-coralmycin A bioavailability values were 61.3% and 11.7%, respectively, after s.c. administration. In a mouse respiratory tract infection model, coralmycin A showed bacteriostatic and bactericidal in vivo efficacies at an s.c. administration of 4 and 100 mg/kg bid, respectively; these efficacies were similar to those of vancomycin at 4 and 20 mg/kg bid, respectively. The present findings indicate that coralmycin A has great potential as a new class of antibiotic for treating infections caused by multidrug-resistant Gram-positive bacteria. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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14 pages, 2610 KiB  
Article
Forced Degradation Studies and Development and Validation of HPLC-UV Method for the Analysis of Velpatasvir Copovidone Solid Dispersion
by Bakht Zaman, Waseem Hassan, Adnan Khan, Ayesha Mushtaq, Nisar Ali, Muhammad Bilal and Dina A. Ahmed
Antibiotics 2022, 11(7), 897; https://doi.org/10.3390/antibiotics11070897 - 5 Jul 2022
Cited by 3 | Viewed by 3503
Abstract
Analytical methods for the drug substance and degradation products (DPs) are validated by performing forced degradation studies. Forced degradation studies of Velpatasvir (VEL) drug substance and Velpatasvir copovidone solid dispersion (VEL-CSD) were performed under the stressed alkaline, acidic, oxidative and thermal conditions according [...] Read more.
Analytical methods for the drug substance and degradation products (DPs) are validated by performing forced degradation studies. Forced degradation studies of Velpatasvir (VEL) drug substance and Velpatasvir copovidone solid dispersion (VEL-CSD) were performed under the stressed alkaline, acidic, oxidative and thermal conditions according to ICH guidelines ICH Q1A (R2). VEL is labile to degrade in stressed alkaline, acidic, and oxidative conditions. It is also photolabile and degraded during photostability studies as described by ICH Q1B, and showed no degradation on exposure to extreme temperature when protected from light. A sensitive stability indicating HPLC-UV method was developed and validated for the separation of VEL and eight DPs. The DPs of VEL are separated using gradient elution of mobile phase containing 0.05% Trifluoroacetic acid (TFA) and methanol over symmetry analytical column C18 (250 mm × 4.6 mm, 5 µm) with a flow rate of 0.8 mL min−1. Simultaneous detection of all DPs and VEL was performed on UV detector at 305 nm. The performance parameters like precision, specificity and linearity of the method were validated using reference standards as prescribed by ICHQ2 (R1). Limits of quantification and limits of detection were determined from calibration curve using the expression 10δ/slope and 3δ/slope respectively. The proposed method is stability-indicating and effectively applied to the analysis of process impurities and DPs in VEL drug substance and VEL-CSD. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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10 pages, 2382 KiB  
Article
Metformin Reverses tmexCD1-toprJ1- and tet(A)-Mediated High-Level Tigecycline Resistance in K. pneumoniae
by Xia Xiao, Quanmin Huan, Yanhu Huang, Yuan Liu, Ruichao Li, Xilan Xu and Zhiqiang Wang
Antibiotics 2022, 11(2), 162; https://doi.org/10.3390/antibiotics11020162 - 27 Jan 2022
Cited by 8 | Viewed by 2945
Abstract
Tigecycline (TIG) is one of the last effective options against multidrug resistance bacteria. Recently, the RND (resistance–nodulation–division) efflux pump gene cluster, tmexCD1-toprJ1, and the tetracycline-efflux pump tet(A) mutation were reported to mediate high level resistance to TIG in clinically important pathogens, [...] Read more.
Tigecycline (TIG) is one of the last effective options against multidrug resistance bacteria. Recently, the RND (resistance–nodulation–division) efflux pump gene cluster, tmexCD1-toprJ1, and the tetracycline-efflux pump tet(A) mutation were reported to mediate high level resistance to TIG in clinically important pathogens, weakening the efficacy of TIG. In this study, we report the potent synergistic effect of the antidiabetic drug metformin in combination with TIG against tet(A) mutant and tmexCD1-toprJ1 positive K. pneumoniae. The fractional inhibitory concentration index (FICI) of TIG and metformin were less than 0.05 for all the tested isolates. The time–kill curve assay showed that the combination of TIG and metformin exhibited much better antimicrobial effect than TIG alone. The synergistic effect was also confirmed in vivo using a well-studied Galleria mellonella larvae model. Mechanistic studies demonstrated that metformin disrupted the important component of proton motive force, the electric potential (Δψ) and the function of efflux pump, thereby increasing the intracellular concentration of TIG. This finding revealed that metformin might be a possible adjuvant of TIG for combating with superbugs carrying the tet(A) mutant and tmexCD1-toprJ1 genes. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)
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