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Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens

The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel st...

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Autores principales: Hussein, Maytham, Hu, Xiaohan, Paulin, Olivia K.A., Crawford, Simon, Tony Zhou, Qi, Baker, Mark, Schneider-Futschik, Elena K., Zhu, Yan, Li, Jian, Velkov, Tony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481501/
https://www.ncbi.nlm.nih.gov/pubmed/32952938
http://dx.doi.org/10.1016/j.csbj.2020.08.008
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author Hussein, Maytham
Hu, Xiaohan
Paulin, Olivia K.A.
Crawford, Simon
Tony Zhou, Qi
Baker, Mark
Schneider-Futschik, Elena K.
Zhu, Yan
Li, Jian
Velkov, Tony
author_facet Hussein, Maytham
Hu, Xiaohan
Paulin, Olivia K.A.
Crawford, Simon
Tony Zhou, Qi
Baker, Mark
Schneider-Futschik, Elena K.
Zhu, Yan
Li, Jian
Velkov, Tony
author_sort Hussein, Maytham
collection PubMed
description The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections).
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spelling pubmed-74815012020-09-17 Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens Hussein, Maytham Hu, Xiaohan Paulin, Olivia K.A. Crawford, Simon Tony Zhou, Qi Baker, Mark Schneider-Futschik, Elena K. Zhu, Yan Li, Jian Velkov, Tony Comput Struct Biotechnol J Research Article The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections). Research Network of Computational and Structural Biotechnology 2020-08-21 /pmc/articles/PMC7481501/ /pubmed/32952938 http://dx.doi.org/10.1016/j.csbj.2020.08.008 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Hussein, Maytham
Hu, Xiaohan
Paulin, Olivia K.A.
Crawford, Simon
Tony Zhou, Qi
Baker, Mark
Schneider-Futschik, Elena K.
Zhu, Yan
Li, Jian
Velkov, Tony
Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title_full Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title_fullStr Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title_full_unstemmed Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title_short Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens
title_sort polymyxin b combinations with fda-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of gram-negative pathogens
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481501/
https://www.ncbi.nlm.nih.gov/pubmed/32952938
http://dx.doi.org/10.1016/j.csbj.2020.08.008
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