Investigating the role of in intrinsic resistance to multiple drugs in .

UNLABELLED

The increasing clinical significance of is owed to its innate high-level, broad-spectrum resistance to antibiotics and therefore rapidly evolves as an important human pathogen. This warrants the identification of novel targets for aiding the discovery of new drugs or drug combinations to treat infections. This study is inspired by the drug-hypersensitive profile of a mutant (U14) with transposon insertion in . We validated the role of in intrinsic drug resistance in by constructing a selectable marker-free in-frame deletion in and complementing the mutant with the same or extended version of the gene and then followed by drug susceptibility testing. Judging by the putative function of MAB_1915, cell envelope permeability was studied by ethidium bromide accumulation assay and susceptibility testing against dyes and detergents. In this study, we established genetic evidence of the role of in intrinsic resistance to rifampicin, rifabutin, linezolid, clarithromycin, vancomycin, and bedaquiline. Disruption of has also been observed to cause a significant increase in cell envelope permeability in . Restoration of resistance is observed to depend on at least 27 base pairs upstream of the coding DNA sequence of . MAB_1915 could therefore be associated with cell envelope permeability, and hence its role in intrinsic resistance to multiple drugs in , which presents it as a novel target for future development of effective antimicrobials to overcome intrinsic drug resistance in .

IMPORTANCE

This study reports the role of a putative fadD (MAB_1915) in innate resistance to multiple drugs by , hence identifying MAB_1915 as a valuable target and providing a baseline for further mechanistic studies and development of effective antimicrobials to check the high level of intrinsic resistance in this pathogen.