bis-Molybdopterin Guanine Dinucleotide Is Required for Persistence of Mycobacterium tuberculosis in Guinea Pigs

Mycobacterium tuberculosisis able to synthesize molybdopterin cofactor (MoCo), which is utilized by numerous enzymes that catalyze redox reactions in carbon, nitrogen, and sulfur metabolism. In bacteria, MoCo is further modified through the activity of a guanylyltransferase, MobA, which converts MoCo tobis-molybdopterin guanine dinucleotide (bis-MGD), a form of the cofactor that is required by the dimethylsulfoxide (DMSO) reductase family of enzymes, which includes the nitrate reductase NarGHI. In this study, the functionality of themobAhomolog inM. tuberculosiswas confirmed by demonstrating the loss of assimilatory and respiratory nitrate reductase activity in amobAdeletion mutant. This mutant displayed no survival defects in human monocytes or mouse lungs but failed to persist in the lungs of guinea pigs. These results implicate one or morebis-MGD-dependent enzymes in the persistence ofM. tuberculosisin guinea pig lungs and underscore the applicability of this animal model for assessing the role of molybdoenzymes in this pathogen.