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Ultra-short antimicrobial peptoids show propensity for membrane activity against multi-drug resistant Mycobacterium tuberculosis

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Title: Ultra-short antimicrobial peptoids show propensity for membrane activity against multi-drug resistant Mycobacterium tuberculosis
Authors: Singh Khara, J
Mojsoska, B
Mukherjee, D
Langford, P
Robertson, B
Ee, PLR
Newton, S
Item Type: Journal Article
Abstract: Tuberculosis (TB) results in both morbidity and mortality on a global scale. With drug resistance on the increase, there is an urgent need to develop novel anti-mycobacterials. Thus, we assessed the anti-mycobacterial potency of three novel synthetic peptoids against drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis in vitro using Minimum Inhibitory Concentration, killing efficacy and intracellular growth inhibition assays, and in vivo against mycobacteria infected BALB/c mice. In addition, we verified cell selectivity using mammalian cells to assess peptoid toxicity. The mechanism of action was determined using flow cytometric analysis, and microfluidic live-cell imaging with time-lapse microscopy and uptake of propidium iodide. Peptoid BM 2 demonstrated anti-mycobacterial activity against both drug sensitive and MDR M. tuberculosis together with an acceptable toxicity profile that showed selectivity between bacterial and mammalian membranes. The peptoid was able to efficiently kill mycobacteria both in vitro and intracellularly in murine RAW 264.7 macrophages, and significantly reduced bacterial load in the lungs of infected mice. Flow cytometric and time lapse fluorescence microscopy indicate mycobacterial membrane damage as the likely mechanism of action. These data demonstrate that peptoids are a novel class of antimicrobial which warrant further investigation and development as therapeutics against TB.
Issue Date: 17-Mar-2020
Date of Acceptance: 27-Feb-2020
URI: http://hdl.handle.net/10044/1/78203
DOI: 10.3389/fmicb.2020.00417
ISSN: 1664-302X
Publisher: Frontiers Media
Start Page: 1
End Page: 11
Journal / Book Title: Frontiers in Microbiology
Volume: 11
Copyright Statement: © 2020 Khara, Mojsoska, Mukherjee, Langford, Robertson, Jenssen, Ee and Newton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: British Society of Antimicrobial Chemotherapy
British Society for Antimicrobial Chemotherapy
Funder's Grant Number: GA2016_009P
GA2016_009P
Keywords: Mycobacterium tuberculosis
anti-mycobacterial
drug resistant
membrane
peptoids
tuberculosis
0502 Environmental Science and Management
0503 Soil Sciences
0605 Microbiology
Publication Status: Published
Article Number: 417
Online Publication Date: 2020-03-17
Appears in Collections:Department of Infectious Diseases