Desiccation-induced DNA damage facilitates drug resistance in .

(Mtb) is an obligate human pathogen that depends on its ability to spread from host-to-host to survive as a species. Yet, knowledge of transmission-specific traits remains lacking. Here, we report the discovery of a specific adaptive response to desiccation, a stress intrinsically linked to the generation of the aerosol droplets within which Mtb transmits. We show that desiccation inflicts oxidative damage and activates Mtb's DNA repair responses but that this repair is imperfect and results in mutations. We further show that activation of these DNA repair responses is accompanied by increased expression of the transcription-coupled repair factor, , but that this expression serves to buffer the fitness cost of specific resistance-conferring mutations in , the target of the frontline drug rifampin, rather than to facilitate transcription-coupled DNA repair. Silencing during aerosolization impairs survival of strains harboring the rifampin resistance allele S450L. This function is further supported by whole genome sequence data from over 50,000 clinically circulating strains. These studies indicate that Mtb has evolved transmission-specific stress responses that have enabled it to leverage desiccation-induced DNA damage as a potential source of genetic diversification and drug resistance.