ABSTRACT Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, currently leads to nearly 1.7 million deaths a year. TB control is threatened by the continued emergence of drug-resistant Mtb strains. Clinical resistance has now been observed against all TB drugs, underscoring the urgent need not just for new drugs, but for entirely new strategies that directly target and disable drug resistance mechanisms. Two of the most promising strategies to prevent the emergence of antibiotic resistance in the treatment of TB are the targeting of drug tolerant, non-replicating bacterial populations and host-directed therapy (HDT). We identified a series of drug-like ATP analogs with in vitro activity against replicating and non-replicating Mtb that is comparable to that of rifampicin, one of the first-line drugs targeting non-replicating Mtb. Because these inhibitors were originally developed for the inhibition of the human transforming growth factor receptor (TGFβR), a pathway implicated in immunity to TB, we also sought to test whether inhibition of TGFβR mediates host-directed activity against Mtb. We found that genetic deletion and chemical inhibition of TGFβR significantly reduced the bacterial load in infected animals. We showed that T-cells lacking TGFβR had an increased capacity to interact in a cognate manner with Mtb-infected macrophages and produce IFNγ at the pulmonary site of infection. These preliminary studies suggest a new answer to the longstanding question why the T cell response to Mtb is inadequate at the site of infection and highlights the possibility that TGFβ signaling is a new HDT target. Thus, we identified compounds that have two independent activities that both kill Mtb and likely impede the emergence of drug resistance. Using genetics and the ATP analogs as chemical tools, we will identify the cellular Mtb targets responsible for directly killing Mtb, thus identifying new targets that underlie drug tolerance. On the host side, we will determine the role of TGFβR signaling in Mtb infection. Lastly, we will test this dual host-pathogen targeting strategy by testing the efficacy of our compounds in vivo.