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dc.contributor.authorHussein, M
dc.contributor.authorHu, X
dc.contributor.authorPaulin, OKA
dc.contributor.authorCrawford, S
dc.contributor.authorTony Zhou, Q
dc.contributor.authorBaker, M
dc.contributor.authorSchneider-Futschik, EK
dc.contributor.authorZhu, Y
dc.contributor.authorLi, J
dc.contributor.authorVelkov, T
dc.date.accessioned2020-11-17T03:35:34Z
dc.date.available2020-11-17T03:35:34Z
dc.date.issued2020
dc.identifierpii: S2001-0370(20)30361-5
dc.identifier.citationHussein, M., Hu, X., Paulin, O. K. A., Crawford, S., Tony Zhou, Q., Baker, M., Schneider-Futschik, E. K., Zhu, Y., Li, J. & Velkov, T. (2020). Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens.. Comput Struct Biotechnol J, 18, pp.2247-2258. https://doi.org/10.1016/j.csbj.2020.08.008.
dc.identifier.issn2001-0370
dc.identifier.urihttp://hdl.handle.net/11343/251551
dc.description.abstractThe 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).
dc.languageeng
dc.publisherElsevier BV
dc.titlePolymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens.
dc.typeJournal Article
dc.identifier.doi10.1016/j.csbj.2020.08.008
melbourne.affiliation.departmentPharmacology and Therapeutics
melbourne.source.titleComputational and Structural Biotechnology Journal
melbourne.source.volume18
melbourne.source.pages2247-2258
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1464008
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481501
melbourne.contributor.authorSchneider, Elena
melbourne.contributor.authorVelkov, Tony
melbourne.contributor.authorHussein, Maytham
dc.identifier.eissn2001-0370
pubs.acceptance.date2020-08-09
melbourne.accessrightsOpen Access


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