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.
Highlights
The emergence and spread of antimicrobial resistance (AMR) is a rapidly growing, global, healthcare threat
An interesting class of antimicrobials are cationic antimicrobial peptides (CAMPS).[15−17] CAMPS are thought to function by interaction with the anionic bacterial cell membrane followed by cell wall permeabilization, or pore formation which leads to cell death, the exact mechanisms are not fully understood and are under debate.[18,19]
It is demonstrated that poly(dimethylaminoethyl methacrylate), PDMAEMA, has potent and selective antimycobacterial activity against a model strain for M. tuberculosis
Summary
The emergence and spread of antimicrobial resistance (AMR) is a rapidly growing, global, healthcare threat. Biomacromolecules extensively reviewed.[22−25] Synthetic polymers are particular appealing as their composition and architecture can be finely tuned using controlled (e.g., radical or ring-opening) polymerization methods and a huge range of monomers are available These have been widely incorporated as biocidal coatings[26] or as mediators of bacteria aggregation and signaling which can effect quorum sensing as well as killing.[27] Fernandez-Trillo and co-workers recently demonstrated that polyionic complexes of an antibacterial polymer with an anionic peptide which upon exposure to elastase secreted by P. aeruginosa released the polymer leading to antibacterial activity, as a new route to targeted antimicrobials.[28]. Transmission electron microscopy (TEM) was performed as previously described.[46] Briefly, M. smegmatis was cultured in TBST for 72 h at 37 °C, 200 rpm. TEM imaging was carried out on a JEOL 2200FS at 200 kV using a Gatan K2 summit camera
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