Enhanced Respiratory Electron Dissipation by Immunometabolites Promotes Mycobacterial Biofilm Longevity

Mycobacterial species inhabit diverse ecological niches and frequently adopt a biofilm lifestyle, including within host environments, where this organization critically influences the persistence and pathophysiological outcomes. Here, using Mycobacterium smegmatis, we demonstrate that nitrate, a host-derived immunometabolite, markedly extends the biofilm lifespan. Mechanistically, nitrate sustains respiratory activity and suppresses the induction of the dormancy response. This effect is accompanied by the maintenance of intracellular redox balance, consistent with enhanced electron dissipation. Importantly, fumarate, a distinct host-relevant metabolite capable of facilitating electron dissipation, recapitulates this phenotype, indicating that the observed biofilm longevity is not limited to nitrate but instead is linked to the availability of alternative electron sinks. Together, our findings establish that the electron dissipation capacity is a key determinant of respiratory homeostasis and biofilm persistence in mycobacteria. We report a similar phenotype for M. abscessus, a nontuberculous opportunistic pathogen. These results highlight respiratory flexibility as a central adaptive axis through which mycobacteria exploit host metabolic cues to prolong survival.