MAT Gain of Activity Mutation in Is Associated with Resistance to MTAN Transition State Analogues.

is found in the gut lining of more than half of the world's population, causes gastric ulcers, and contributes to stomach cancers. Menaquinone synthesis in relies on the rare futalosine pathway, where 5'-methylthioadenosine nucleosidase (MTAN) is proposed to play an essential role. Transition state analogues of MTAN, including BuT-DADMe-ImmA (BTDIA) and MeT-DADMe-ImmA (MTDIA), exhibit bacteriostatic action against numerous diverse clinical isolates of with minimum inhibitory concentrations (MIC's) of <2 ng/mL. Three BTDIA-resistant clones were selected under increasing BTDIA pressure. Whole genome sequencing showed no mutations in MTAN. Instead, resistant clones had mutations in , methionine adenosyltransferase (MAT), , a regulator of the iron transport system, and , a flagellar synthesis regulator. The mutation in causes expression of a MAT with increased catalytic activity, leading to elevated cellular -adenosylmethionine. Metabolite analysis and the mutations associated with resistance suggest multiple inputs associated with BTDIA resistance. Human gut microbiome exposed to MTDIA revealed no growth inhibition under aerobic or anaerobic conditions. Transition state analogues of MTAN have potential as agents for treating infection without disruption of the human gut microbiome or inducing resistance in the MTAN target.