ABSTRACT Tuberculosis (TB) is both among the most transmissible causes of death and the leading cause of death due to an infectious disease worldwide, making it the leading cause of death due to a curable disease. Control of the pandemic thus requires not only faster and more effective diagnostic tests and cures, but also novel and specific transmission blocking interventions. This project focuses on the latter, and seeks to identify conserved and specific metabolic processes in Mycobacterium tuberculosis (Mtb), the causative agent of TB, whose inhibition has the potential to impair its survival during transmission from one host to the next. This project specifically leverages Mtb's exclusive evolutionary history in humans as both host and only known reservoir, which has made transmission not only an essential feature of its pathogenicity but intrinsic phase of its life cycle that is essential for its survival as a species. Despite its erratic and seemingly heterogeneous nature, all transmission events involve a number of transitions, such as changes in gas composition and desiccation stress, that are comparatively invariant and highly repetitive in nature. We hypothesize that these changes have resulted in the evolutionary selection of specific and adaptive metabolic responses in Mtb that have equipped it to predictably complete this essential but erratic phase of its life cycle, inhibition of which might slow or prevent its spread. This project builds on preliminary data which have identified several such responses and, in collaboration with other Projects and Cores in this Program Project, will now test their essentiality for survival in a series of in vitro and animal models of aerosol transmission, and clinical relevance as reported by clinical Mtb isolates recovered from epidemiologically defined settings and inferred levels of transmissibility.