Impaired ESX‐3 Induces Bedaquiline Persistence in Mycobacterium abscessus Growing Under Iron‐Limited Conditions

Abstract ESX‐3 is a secretion pathway which is essential for mycobactin‐mediated iron acquisition under iron‐limited conditions. Although present in all Mycobacterium sp ., ESX‐3 remains to be elucidated in Mycobacterium abscessus . In the study reported here, impaired ESX‐3 seriously restricts the growth of M. abscesses under iron‐limited conditions; growth is salvaged by functional ESX‐3 or iron supplementation. Notably, impaired ESX‐3 does not kill M. abscesses when environmental iron is insufficient but induces persistence to bedaquiline, a diarylquinoline class antibiotic used to treat multidrug‐resistant mycobacteria. One potential mechanism contributing to persistence is the iron deficiency due to impaired ESX‐3 suppressing succinate dehydrogenase activity, which dysregulates the tricarboxylic acid cycle and inactivates bedaquiline. Experiments conducted here also demonstrate that the regulator, MtrA, can bind ESX‐3 and promote the survival of M. abscessus . As such, this study suggests that a novel pathway involving MtrA, ESX‐3, iron metabolism, and the TCA cycle contributes to bedaquiline persistence in M. abscesses growing under iron‐limited conditions.