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Due to the significant increase in the antimicrobial resistance of Gram-negative bacilli (GNB), the development of non-antimicrobial therapeutic alternatives, which can be used together with the few and non-optimal available antimicrobial agents such as colistin, has become an urgent need. In this context, the desregulation of the bacterial cell wall could be a therapeutic alternative adjuvant to colistin. The aim of this study was to analyse the activity of oxyclozanide, an anthelmintic drug, in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB. Three reference Col-S strains and 13 Col-R clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were studied. Microdilution assays and time-kill curves were performed to examine the activity of oxyclozanide in combination with colistin. Outer membrane proteins (OMPs) profile, membrane permeation and cell wall structure of Col-S and Col-R A. baumannii, P. aeruginosa and K. pneumoniae in presence of oxyclozanide were assessed by SDS-PAGE, fluorescence and transmission electron microscopy, respectively. Oxyclozanide in combination with colistin increases the activity of colistin against Col-S and Col-R A. baumannii, P. aeruginosa and K. pneumoniae. Time-killing curves have showed synergistic activity between oxyclozanide and colistin against these bacterial isolates. Moreover, Col-R A. baumannii, P. aeruginosa and K. pneumoniae in presence of oxyclozanide present higher permeation and disruption in their cell wall than Col-S strains, without modifying their OMPs profile. These data suggest that the combination of oxyclozanide and colistin may be a new alternative for the treatment of Col-R GNB infections.
This article was published in the following journal.
Name: International journal of antimicrobial agents
Repurposing nonantibiotic drugs for antimicrobial therapy presents a viable approach to drug discovery. Development of therapeutic strategies that overcome existing resistance mechanisms is important ...
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Cyclic polypeptide antibiotic from Bacillus colistinus. It is composed of Polymyxins E1 and E2 (or Colistins A, B, and C) which act as detergents on cell membranes. Colistin is less toxic than Polymyxin B, but otherwise similar; the methanesulfonate is used orally.
Anthelmintic used in grazing animals for fasciola and cestode infestations.
Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase. It has been proposed for infections with gram-negative and gram-positive organisms, GONORRHEA, and HAEMOPHILUS.
A semisynthetic cephamycin antibiotic that is administered intravenously or intramuscularly. The drug is highly resistant to a broad spectrum of beta-lactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative microorganisms.
A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with gram-positive organisms.
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