A cationic main-chain poly(carbonate-imidazolium) potent against Mycobacterium abscessus and other resistant bacteria in mice

Abstract

The incidence of serious lung infections due to Mycobacterium abscessus, a worrying non-tuberculosis mycobacteria (NTM) species, is rising and has in some countries surpassed tuberculosis. NTM are ubiquitous in the environment and can cause serious lung infections in people who are immunocompromised or have pre-existing lung conditions. M. abscessus is intrinsically resistant to most antibiotics. Current treatments involve combination of three or more repurposed antibiotics with the treatment regimen lasting at least 12 months but producing unsatisfactory success rates of less than 50 %. Herein, we report an alternative strategy using a degradable polymer, specifically main-chain cationic carbonate-imidazolium-derived polymer (MCOP-1). MCOP-1 is a non-toxic agent active in a murine lung infection model. MCOP-1 also exhibits excellent efficacy against multi-drug resistant (MDR) ESKAPE bacteria. MCOP-1 damages bacterial membrane and DNA, and serial passaging does not rapidly elicit resistance. Its carbonate linkage is stable enough to allow MCOP-1 to remain intact for long enough to exert its bactericidal effect but is labile over longer time periods to degrade into non-toxic small molecules. These findings underscore the potential of degradable MCOP-1 as a promising therapeutic antimicrobial agent to address the growing incidence of recalcitrant infections due to M. abscessus and MDR ESKAPE bacteria.