title: Evaluation of the Antimicrobial Activity of Cationic Polymers against Mycobacteria: Toward Antitubercular Macromolecules.
abstract: Antimicrobial resistance is a global healthcare problem with a dwindling arsenal of usable drugs. Tuberculosis, caused by Mycobacterium tuberculosis, requires long-term combination therapy and multi- and totally drug resistant strains have emerged. This study reports the antibacterial activity of cationic polymers against mycobacteria, which are distinguished from other Gram-positive bacteria by their unique cell wall comprising a covalently linked mycolic acid-arabinogalactan-peptidoglycan complex (mAGP), interspersed with additional complex lipids which helps them persist in their host. The present study finds that poly(dimethylaminoethyl methacrylate) has particularly potent antimycobacterial activity and high selectivity over two Gram-negative strains. Removal of the backbone methyl group (poly(dimethylaminoethyl acrylate)) decreased antimycobacterial activity, and poly(aminoethyl methacrylate) also had no activity against mycobacteria. Hemolysis assays revealed poly(dimethylaminoethyl methacrylate) did not disrupt red blood cell membranes. Interestingly, poly(dimethylaminoethyl methacrylate) was not found to permeabilize mycobacterial membranes, as judged by dye exclusion assays, suggesting the mode of action is not simple membrane disruption, supported by electron microscopy analysis. These results demonstrate that synthetic polycations, with the correctly tuned structure are useful tools against mycobacterial infections, for which new drugs are urgently required.
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Phillips
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Harrison
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Richards
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mitchell
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Tichauer
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Alasdair T M
authors.initials: ATM
authors.lastname: Hubbard
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Collette
authors.initials: C
authors.lastname: Guy
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Hands-Portman
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fullam
authors.affiliation: Department of Chemistry, ‡School of Life Sciences, and §Warwick Medical School, University of Warwick , Coventry, CV4 7AL, United Kingdom.
authors.forename: Matthew I
authors.identifier: http://orcid.org/0000-0002-8297-1278
authors.initials: MI
authors.lastname: Gibson
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis; D008689:Methacrylates / Q000737:chemistry* / Q000494:pharmacology; D009161:Mycobacterium / Q000187:drug effects*; D009757:Nylons / Q000737:chemistry* / Q000494:pharmacology; D011073:Polyamines / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D000071228:Polyelectrolytes
chemical_list: D000995:Antitubercular Agents; D008689:Methacrylates; D009757:Nylons; D011073:Polyamines; D000071228:Polyelectrolytes; C407037:poly(2-(dimethylamino)ethyl methacrylate)