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The upstream region of Mycobacterium abscessus whiB7 as a culprit for poor treatment outcome?

N De Boeck(1,2,3) N Verstraeten(1,2) J Michiels(1,2)

1:KU Leuven - Centre of Microbial and Plant Genetics; 2:VIB - Center for Microbiology; 3:J&J - Innovative Medicine R&D

Mycobacterium abscessus infections can be considered as an antibiotic nightmare. Treatment efficacy is hampered by its intrinsic and acquired drug resistance, and relapse or reinfection occur frequently. Prolonged multidrug regimes with different antibiotic classes are recommended to eradicate surviving bacteria and improve treatment outcomes. While different stress responses and mechanisms have been implicated in M. abscessus drug survival, underlying genetic causes remain poorly understood.

The aim of the current study was to explore these causes in M. abscessus by identifying and characterizing genetic mutations that affect survival during in vitro evolution experiments and to investigate their role in resistance. To this end, bacterial cultures were exposed to amikacin and rifabutin for 7 days, after which surviving cells were washed, passaged and treated again with the same antibiotic combination. Clonal and bulk populations were subjected to whole genome sequencing to identify mutations and genes involved in drug survival.

One frameshift mutation in mab_3509c was found to induce a stress response similar to the previously described macrolide-induced stress response. Interestingly, the frameshift results both in increased survival in the drug combination treatment and increased minimal inhibitory concentrations of amikacin and clarithromycin. It is located upstream of the mab_3508c gene encoding transcriptional regulator WhiB7, a well-known determinant of multi-drug resistance. Our findings highlight the importance of the upstream region in inducing the mycobacterial whiB7 stress response. More insight in the regulation of drug resistance will be instrumental in devising future therapies to treat M. abscessus infections.

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