Cyclophostin and Cyclipostins analogues counteract macrolide-induced resistance mediated by Erm(41) in Mycobacterium abscessus

Mycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, including clarithromycin (CLR) and azithromycin (AZM), represent the current cornerstone of antibiotherapy against M. abscessus complex. However, prolonged exposure to macrolides can induce the apparition of Erm(41)-mediated resistance, limiting their spectrum of activity and often leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility and avoid the therapeutic failure. In a previous study, the Erm(41) methyltransferase was identified as a target enzyme of Cyclipostins and Cyclophostin compounds (CyC). Herein, we took advantage of this feature to evaluate the in vitro activity of clarithromycin and azithromycin in combination with different CyC via the checkerboard assay on macrolide susceptible and induced macrolide-resistant M. abscessus generated by either clarithromycin or azithromycin exposure. Our results emphasize the use of the CyC to prevent/overcome Erm(41) induced resistance, restore macrolide susceptibility. This work should help to expand our therapeutic arsenal in the fight against a particularly antibiotic resistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in CF patients, and particularly in erm(41)-positive strains.