Strategies to elucidate the mode of action of the avermectins against mycobacteria
Presentation talk given by Jose Manuel Ezquerra
New active compounds are urgently required for the treatment of tuberculosis (TB). Repurposing, i.e., finding new applications for existing drugs, can be a quick alternative to the traditional discovery process. By using this approach, the avermectins, a family of anthelmintic compounds previously believed to be inactive against bacteria, were found to be effective against Mycobacterium tuberculosis and other mycobacteria (PMID: 23165468, 26270480). However, their antimycobacterial mode of action remains unknown.
We first characterized the in vitro antimicrobial activity of selamectin, a model avermectin, against the non-pathogenic Mycolicibacterium smegmatis and attempted isolation of resistant mutants with the wild-type strain and a pool of transposition mutants. However, only when the hypermutator strain M. smegmatis ∆nucS (PMID: 28128207) was used, we were able to isolate low-level selamectin-resistant mutants showing a 2-fold increase of the MIC (Minimal Inhibitory Concentration) of selamectin. Subsequent rounds of selection using the previously isolated low-level selamectin resistant strains yielded high-level resistant mutants (>8-fold MIC changes).
In this presentation we aim to shed light on the mode of action of the avermectins and will report the current progress on the characterization of their antimycobacterial activity.