Vancomycin rescues sensitivity to isoniazid in clinical isolates of drug-resistant Mycobacterium tuberculosis

ABSTRACT Tuberculosis (TB) continues to be a major global health challenge, with a particularly high incidence of antibiotic resistance in high-burden countries. The increasing prevalence of resistance in Mycobacterium tuberculosis ( Mtb ) to both first-line and second-line TB drugs calls for novel approaches to address this problem. Tackling antibiotic-resistance at its source, with treatment strategies that can reverse resistance or control its new emergence, would be promising in the long run. Our previous work with lab-evolved isoniazid-resistant Msmeg showed that resistant bacteria have a diminished capacity to counter oxidative stress, causing them to be sensitive to several drugs like ebselen, phenylarsine oxide, vancomycin, all of which are known to affect redox homeostasis in mycobacteria. In this work, we report the efficacy of the combination, isoniazid+vancomycin (INH+VAN), on several drug-resistant clinical isolates of Mtb with varying resistance profiles, isolated from patient sputum samples. We also show that vancomycin is able to rescue sensitivity to isoniazid in a drug-resistant clinical strain of Mtb in a murine infection model. Furthermore, by combining transcriptomic analysis and systems-level modeling, we identify that this efficacy is possibly due to a vulnerability arising from cell wall alterations and stress responses during INH-VAN treatment. Our results suggest that the combination INH+VAN is promising by itself or as part of the standard regimens for treating drug-resistant TB cases, and therefore suitable for a clinical trial in isoniazid-resistant and MDR TB cases. IMPORTANCE Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis ( Mtb ), which claims millions of lives each year, posing a global health challenge. While there are several antibiotic therapies available, resistance to primary drugs severely hinders successful TB treatment. This calls for novel treatment strategies against drug-resistant TB. We have identified a strategy to reverse resistance by addition of a strategically selected repurposable antibiotic that targets the resistance-generating mechanism. Our study demonstrates that vancomycin, in combination with isoniazid, reverses isoniazid resistance and is effective in killing drug-resistant Mtb . Since isoniazid is a primary TB drug, and vancomycin is already in clinical use for the treatment of common bacterial infections, they can easily be introduced as a combination into the pipeline for TB treatment. Our work addresses the urgent need for newer TB treatment strategies and provides data indicating the potential for a clinical trial in MDR TB cases.