Mycobacterium abscessus activates cross-resistance following antibiotic exposure

Abstract

Mycobacterium abscessus lung disease is extremely difficult to treat, with treatment success rates as low as 50%. A deeper understanding of underlying resistance mechanisms is pivotal in development of novel targeted therapeutic regimens. To facilitate this, we elucidated the stress-induced transcriptomic response of M. abscessus to all drugs included in current treatment guidelines. M. abscessus CIP104536 bacteria in early log-phase were subjected to sub-inhibitory concentrations of clarithromycin (CLR), amikacin (AMK), tigecycline (TIG), and cefoxitin (FOX) for 24h, followed by RNA sequencing. Subsequently, MIC determination and time-kill kinetic analysis was performed following 24h of exposure to CLR, AMK or TIG. An induction of the whiB7 resistome was observed following CLR, AMK and TIG exposure, whereas further transcriptomic responses were highly drug-specific (Figure panel A). In line with this finding, eis2 and erm(41), whiB7-associated genes conferring AMK and CLR resistance, were also induced. Subsequent MIC determination and time-kill kinetic analyses showed pre-incubation with CLR, AMK and TIG led to decreased susceptibility to both AMK and CLR (Figure panel B+C). Pre-exposure to whiB7-inducing antibiotics leads to decreased susceptibility to AMK and CLR. In clinical practice, exposure to these groups of antibiotics prior to M. abscessus treatment should be avoided, as it may hinder subsequent therapeutic success.