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Latest Progress in the Polymyxin Class of Antibiotics

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 8053

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Special Issue Editors

Prof. Dr. Jian Li

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Guest Editor

Biomedicine Discovery Institute, Monash University, Melbourne, Australia
Interests: discovery of novel antimicrobials; antimicrobial systems pharmacology; pharmacokinetics, pharmacodynamics and toxicodynamics of antibiotics; mechanisms of activity, resistance, and toxicity of polymyxins; novel formulations for inhalation and parenteral administration of antibiotics

Dr. Xukai Jiang

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Guest Editor

National Glycoengineering Research Center, Shandong University, Qingdao, Shandong, China
Interests: molecular dynamics simulation techniques; integrating chemical and molecular biology approaches

Dr. Nusaibah Abdul Rahim

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Guest Editor

Head, Department of Clinical Pharmacy & Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
Interests: pharmacy

Special Issue Information

Dear Colleagues,

Antibiotic resistance is an urgent global health threat. In particular, multidrug-resistant Gram-negative ‘superbugs’ (e.g., Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii) represent the gravest challenges due to their resistance to almost all current antibiotics. As an old class of lipopeptide antibiotics, polymyxins (i.e., polymyxin B and colistin) are increasingly used as a last-line of clinical therapy against these life-threatening ‘superbugs’.

In recent years, significant efforts have been made to understand the mechanisms of antibacterial activity, resistance and toxicity found in polymyxin antibiotics, as well as to optimize their clinical use. This Special Issue focuses on the important polymyxin class of antibiotics and will consist of a variety of papers, including original research, review articles, case series, and opinion papers. This Special Issue covers both clinical and mechanistic studies of polymyxins in the following areas:

Mechanisms of polymyxin antimicrobial activity;
Mechanisms of bacterial resistance to polymyxins;
Mechanisms of polymyxin-induced toxicity;
The molecular design of novel polymyxins;
The discovery of novel polymyxin-like antibiotics;
The clinical usage of polymyxins (dose optimisation, therapeutic drug monitoring, adverse effects);
The combination therapy of polymyxins with other antibiotics/non-antibiotics;
Breakpoints of polymyxins;
Novel formulations of polymyxins.

Prof. Dr. Jian Li
Dr. Xukai Jiang
Dr. Nusaibah Abdul Rahim
Guest Editors

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

polymyxins
combination therapy
dose optimisation
nephrotoxicity

Published Papers (4 papers)

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Research

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27 pages, 4080 KiB

Open AccessArticle

Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant Acinetobacter baumannii

by Filomena Sannio, Antonella Brizzi, Rosita Del Prete, Marialuce Avigliano, Tiziana Simone, Carlotta Pagli, Teresa Ferraro, Filomena De Luca, Marco Paolino, Federico Corelli, Claudia Mugnaini and Jean-Denis Docquier

Antibiotics 2022, 11(12), 1832; https://doi.org/10.3390/antibiotics11121832 - 16 Dec 2022

Cited by 3 | Viewed by 1425

Abstract

The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. Acinetobacter baumannii isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant A. baumannii as a “critical priority” for the discovery and development of new antibacterial agents. In a previous work, we identified several series of compounds showing either direct-acting or synergistic activity against relevant Gram-negative species, including A. baumannii. Among these, two pyrazole compounds, despite being devoid of any direct-acting activity, showed remarkable synergistic activity in the presence of a subinhibitory concentration of colistin on K. pneumoniae and A. baumannii and served as a starting point for the synthesis of new analogues. In this work, a new series of 47 pyrazole compounds was synthesized. Some compounds showed significant direct-acting antibacterial activity on Gram-positive organisms. Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR Acinetobacter baumannii, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens. Full article

(This article belongs to the Special Issue Latest Progress in the Polymyxin Class of Antibiotics)

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11 pages, 679 KiB

Open AccessArticle

Evaluation of Agar Dilution Method in Susceptibility Testing of Polymyxins for Enterobacteriaceae and Non-Fermentative Rods: Advantages Compared to Broth Microdilution and Broth Macrodilution

by Xinxin Hu, Lilan Sun, Tongying Nie, Yan Yang, Xiukun Wang, Jing Pang, Xi Lu, Xue Li, Yun Lu, Congran Li, Xinyi Yang, Yao Meng, Guoqing Li and Xuefu You

Antibiotics 2022, 11(10), 1392; https://doi.org/10.3390/antibiotics11101392 - 11 Oct 2022

Viewed by 2125

Abstract

An accurate and reliable susceptibility testing method for polymyxins is urgently needed not only for the clinical laboratory but also for new polymyxin-like lipopeptide development. Reference broth microdilution (rBMD), which was the recommended method by CLSI-EUCAST in clinics, has been proven not to be ideal, while the agar dilution (AD) method that was widely used in new antibiotics discovery has been neglected. In the present study, the AD method was compared with rBMD and broth macrodilution (BMAD) in susceptibility testing of polymyxin B and colistin against >200 Gram-negative isolates. AD showed strong agreement with BMAD for colistin (except for Klebsiella aerogenes and Pseudomonas aeruginosa); however, its performance was poor for polymyxin B or compared to rBMD. MICs of AD method were not affected when different types of Petri dishes were used, while glass-bottom microtiter plates could lower the MIC of polymyxins 2–8 times compared to tissue-culture-treated polystyrene plates when using rBMD, which demonstrated that tissue-culture-treated plates were not suitable. It was then validated with non-tissue-culture-treated plates. The culture volume was another influencing factor of accuracy for rBMD, and 200 μL seemed to be the most suitable volume for MIC detection of polymyxins. Additionally, no lack of growth phenomenon (skipped well) was observed for AD when it frequently occurred for both BMAD and rBMD. As for strains carrying mcr-1 gene, 100% of AD results were in essential agreement (EA) and categorical agreement (CA) with both rBMD and BMAD. Overall, rBMD is convenient and widely accepted for susceptibility testing of polymyxins. Although it may be too early to say that AD is superior compared to rBMD and BMAD, it did show some advantages in repeatability and anti-interference ability. Full article

(This article belongs to the Special Issue Latest Progress in the Polymyxin Class of Antibiotics)

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14 pages, 1311 KiB

Open AccessArticle

mcr-1-Mediated In Vitro Inhibition of Plasmid Transfer Is Reversed by the Intestinal Environment

by Xiaoman Yang, Rundong Shu, Leqi Hou, Panpan Ren, Xin Lu, Zhi Huang, Zengtao Zhong and Hui Wang

Antibiotics 2022, 11(7), 875; https://doi.org/10.3390/antibiotics11070875 - 29 Jun 2022

Cited by 1 | Viewed by 1656

Abstract

Colistin is regarded as an antibiotic of last resort against multidrug-resistant Gram-negative bacteria, including Klebsiella pneumoniae and Escherichia coli. Colistin resistance is acquired by microorganisms via chromosome-mediated mutations or plasmid-mediated mobile colistin resistance (mcr) gene, in which the transfer of mcr is the predominant factor underlying the spread of colistin resistance. However, the factors that are responsible for the spread of the mcr gene are still unclear. In this study, we observed that mcr-1 inhibited the transfer of the pHNSHP45 backbone in liquid mating. Similar inhibitory effect of mcr-1.6 and chromosomal mutant ΔmgrB suggested that colistin resistance, acquired from either plasmid or chromosomal mutation, hindered the transfer of colistin resistance-related plasmid in vitro. Dual plasmid system further proved that co-existing plasmid transfer was reduced too. However, this inhibitory effect was reversed in vivo. Some factors in the gut, including bile salt and anaerobic conditions, could increase the transfer frequency of the mcr-1-containing plasmid. Our results demonstrated the potential risk for the spread of colistin resistance in the intestine, provide a scientific basis against the transmission of colistin resistance threat. Full article

(This article belongs to the Special Issue Latest Progress in the Polymyxin Class of Antibiotics)

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Review

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17 pages, 1300 KiB

Open AccessReview

Next-Generation Polymyxin Class of Antibiotics: A Ray of Hope Illuminating a Dark Road

by Abdullah Tarık Aslan, Murat Akova and David L. Paterson

Antibiotics 2022, 11(12), 1711; https://doi.org/10.3390/antibiotics11121711 - 27 Nov 2022

Cited by 10 | Viewed by 2323

Abstract

Although new-generation antimicrobials, in particular β-lactam/β-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review. Full article

(This article belongs to the Special Issue Latest Progress in the Polymyxin Class of Antibiotics)

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