Investigating the composition and recruitment of the mycobacterial ImuA'-ImuB-DnaE2 mutasome

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial mutasome' - minimally comprising DnaE2 polymerase and ImuA ' and ImuB accessory proteins - remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III beta subunit (beta clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuB(AAAAGG) mutant containing a disrupted beta clamp-binding motif abolishes ImuB-beta clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this beta clamp-binding antibiotic collapses pre-formed ImuB-beta clamp complexes. These observations establish the essentiality of the ImuB-beta clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.

Automated summary

A study found that a DNA damage-inducible mutagenic gene cassette is involved in the emergence of drug resistance in Mycobacterium tuberculosis. The study also revealed the molecular composition and operation of the encoded 'mycobacterial mutasome'. These findings provide a new target for the development of adjunctive therapeutics to protect anti-TB drugs against emerging resistance.