Drug resistance in bacterial pathogens is often the result of mutations in core-biological pathways, leading to disrupted protein function and imposing a fitness cost on the cells. We hypothesize that understanding the costs of drug resistance and how drug-resistant strains adapt to mutations to limit these costs may identify unique therapeutic vulnerabilities. To address this hypothesis, we used Mycobacterium tuberculosis as a model bacterium and generated mutants that were resistant to the frontline tuberculosis drug isoniazid. Mutations in KatG, a bifunctional catalase-peroxidase, were the primary cause of INH-resistance (INHR) in our resistant isolates. We used whole genome CRISPRi screens to generate a genome-wide map of cellular vulnerabilities in a M. tuberculosis katG mutant. We discovered that loss of KatG function generates cellular vulnerabilities in protein synthesis and amino acid metabolism. These vulnerabilities were more sensitive to inhibition in an INHR katG mutant under in vitro and host-relevant conditions and translated to clinical populations. Combined, this work highlights how changes in the physiology of INHR strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes.