Polypharmacology in multi-drug-resistant tuberculosis: current scenario and future promise

Tuberculosis (TB) remains the world's leading infectious killer, and the growing threat of anti-TB drug resistance has intensified the urgency for innovative therapeutic strategies. Polypharmacology offers a remarkable solution, enabling a single drug to hit multiple essential targets, thereby achieving higher efficacy and suppressing resistance evolution more effectively than classical single-target drugs. This review discusses the contemporary strategies for designing such polypharmacological agents for TB, distinguishing between the linker, fused, and merged-hybrid design approaches. Representative scaffolds in the TB pipeline are critically evaluated to highlight both the progress and persistent translational gaps. Notably, although numerous hybrid molecules exhibit potent in vitro activity, only a small fraction have advanced to in vivo evaluation, and none have yet reached clinical trials. This marks the need for a better pipeline to design, synthesise, optimise and evaluate such compounds. We also discuss a merged hybrid scaffold built from cinnamoyl and pyrone moieties to illustrate how intentional hybrid design can encode the potential for multi-target engagement, where phenotypic activity offers preliminary mechanistic insight; nonetheless, target validation remains essential for true polypharmacology. We also delineate the practical limitations of the current discovery practices and outline a step-by-step pipeline to accelerate promising polypharmacological scaffolds to pre-clinical testing and, ultimately, clinical development.