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.

Green Fabrication of Amphiphilic Quaternized β‐Chitin Derivatives with Excellent Biocompatibility and Antibacterial Activities for Wound Healing

“…Antibiotics are the most widely used treatment for bacterial infection, and they operate by inhibiting specific biosynthetic pathways of DNA replication and repair, protein synthesis, and cell wall turnover; however, the wide and indiscriminate use of antibiotics has led to the increasing problem of antibiotic‐resistant pathogens . Great efforts have been dedicated to the treatment of bacterial infection, as reflected by the continuing and extensive development of antimicrobial materials, including antimicrobial nanomaterials, antimicrobial peptides,[1b,4] and cationic polymers . An ideal antimicrobial material for clinical applications should exhibit broad‐spectrum and efficient antimicrobial properties, low toxicity to mammalian cells, and high selectivity for bacterial cells over human red blood cells.…”

“…An ideal antimicrobial material for clinical applications should exhibit broad‐spectrum and efficient antimicrobial properties, low toxicity to mammalian cells, and high selectivity for bacterial cells over human red blood cells. [5b,6] Natural antimicrobial peptides are cationic and often form amphiphilic structures. They consistently form tubular structures or bundles and are preferentially attracted to the negatively charged surfaces of bacteria over neutral zwitterionic mammalian cell membranes, resulting in the disruption of bacterial membranes to break the transmembrane potential and leak the cytoplasmic contents and ultimately in bacteria death.…”

“…[4b,7] Antimicrobial peptides have a low propensity for the development of resistance in bacteria; however, the clinical implementation of antimicrobial peptides has suffered from poor in vivo antimicrobial activity, salt instability, high cost, high hemolysis, and high toxicity. [7d,8] Inspired by the cationic charge and amphiphilic structure of antimicrobial peptides, numerous cationic polymers have been designed and synthesized, including polyacrylates, poly(ionic liquid)s,[5d,10] polycarbonates, and polynorbornenes . Some cationic polymer scaffolds are nonbiodegradable, and their preparation from monomers generally requires complicated chemical synthesis and purification processes involving organic solvents or toxic catalysts, which reduces their antimicrobial efficiency and biocompatibility .…”

“…[15a,16] Therefore, many water‐soluble chitosan derivatives, especially quaternized chitosan derivatives, have been synthesized as good candidates for polycationic biocides. [5c,17] However, this approach always involves multistep procedures and organic solvents under heterogeneous conditions. Typically, water‐soluble quaternized chitosan derivatives are synthesized from chitosan either by N ‐alkylation via a Schiff's base intermediate, followed by quaternization with other alkylating reagents such as methyl iodide, or directly by using other quaternizing agents such as glycidyltrimethylammonium chloride.…”

“…Typically, water‐soluble quaternized chitosan derivatives are synthesized from chitosan either by N ‐alkylation via a Schiff's base intermediate, followed by quaternization with other alkylating reagents such as methyl iodide, or directly by using other quaternizing agents such as glycidyltrimethylammonium chloride. [5c,18]…”