Abstract

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, caused by *Mycobacterium tuberculosis* (Mtb), presents a critical global health challenge. A key mechanism contributing to this resistance is the active efflux of anti-tuberculosis drugs mediated by various membrane-bound efflux pumps (EPs). These EPs, which are integral to the Mtb cell membrane, actively transport drugs out of the bacterial cell, thereby reducing their intracellular concentration and therapeutic efficacy. This review explores the **prospects and obstacles for the clinical use of efflux pump inhibitors (EPIs)** as a novel adjunctive therapy. The primary objective is to evaluate the potential of EPIs to restore or enhance the susceptibility of Mtb to existing first- and second-line drugs. Key findings from preclinical studies indicate that EPIs can significantly potentiate the activity of drugs like isoniazid and rifampicin, often by targeting the proton motive force that energizes these membrane transporters. However, the translation of these promising results into clinical practice faces significant hurdles, including the need for EPIs with high specificity, low host toxicity, and the ability to penetrate the mycobacterial cell wall and reach the membrane-embedded EPs. Furthermore, the complex and redundant nature of the Mtb efflux system necessitates the development of broad-spectrum EPIs or combination therapies. Overcoming these pharmacological and biological obstacles is essential to unlock the full potential of EPIs in shortening treatment regimens and combating drug-resistant tuberculosis.