Study identifies genetic basis of rifamycin resistance in Mycobacterium abscessus and reveals potential combination therapy strategies
Researchers used transposon insertion sequencing (Tn-Seq) to map the genetic determinants of intrinsic rifampicin resistance in Mycobacterium abscessus, a bacterium notorious for resisting most antibiotics. The screen confirmed known resistance genes and uncovered new ones, particularly implicating cell envelope processes and an efflux pump gene (MAB_2807) as major contributors. The findings suggest that pairing rifamycins with specific beta-lactam antibiotics could offer a rational combination strategy against this difficult-to-treat pathogen.
Mycobacterium abscessus is an opportunistic pathogen that is intrinsically resistant to a broad range of antibiotics, including rifampicin, a cornerstone drug used against tuberculosis, leaving clinicians with very limited treatment options. To systematically identify the genes responsible for this resistance, the researchers applied Tn-Seq—a high-throughput method that disrupts individual genes across the entire genome and measures which disruptions sensitize the bacterium to the drug. The screen confirmed previously known resistance determinants such as arr, helR, and MAB_2807, while also revealing many novel contributors, particularly genes involved in cell envelope biosynthesis and maintenance. Targeted deletion and insertion mutants of seven representative genes validated the screen's findings, with MAB_2807 emerging as a key efflux pump whose disruption led to measurably higher intracellular rifampicin accumulation. Notably, the resistance mechanisms in M. abscessus were found to be distinct from those in M. tuberculosis, underscoring species-specific biology. Guided by the cell-envelope genetic signature, the team demonstrated selective synergistic interactions between rifamycins and specific beta-lactam antibiotics. Mechanistically, rifampicin exposure was also shown to alter cell envelope ultrastructure and increase accumulation of the peptidoglycan precursor UDP-N-acetylglucosamine, pointing to envelope-associated metabolic disruption as a potential vulnerability to exploit therapeutically.
What's missing
As a preprint on bioRxiv, this study has not yet undergone formal peer review, so findings should be interpreted with caution. The study was conducted in vitro and in bacterial culture models; it is unclear whether the identified synergistic rifamycin/beta-lactam combinations will translate to in vivo efficacy or clinical settings. The clinical relevance of MAB_2807 disruption as a therapeutic target also remains to be established, as pharmacological inhibition of this efflux pump has not yet been demonstrated.
What different sources said
- bioRxivCenter
Transposon insertion sequencing identifies genetic determinants of intrinsic rifamycin resistance in Mycobacterium abscessus
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