Mycobacterium tuberculosis efflux pumps (Mtb efflux pumps)

Mycobacterium tuberculosis efflux pumps are specialized membrane proteins that actively expel a variety of toxic substances, including antibiotics, from the bacterial cytoplasm to the extracellular environment. These transporters are categorized into five primary families: the ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the resistance-nodulation-division (RND) family, the small multidrug resistance (SMR) family, and the multidrug and toxic compound extrusion (MATE) family (Remm et al., 2022). Their primary biological role involves maintaining cellular homeostasis and transporting essential cell wall components, but they are also major contributors to the intrinsic and acquired drug resistance observed in tuberculosis (Machado et al., 2012). By reducing the effective intracellular concentration of frontline drugs such as isoniazid and rifampicin, these pumps allow the bacteria to survive sub-lethal antibiotic exposure, often leading to the development of high-level genetic resistance (Szumowski et al., 2013). Consequently, these pumps are considered significant therapeutic targets; inhibiting them can potentially restore antibiotic sensitivity and shorten the duration of tuberculosis treatment (Sharma et al., 2019). Current research focuses on developing efflux pump inhibitors (EPIs) like verapamil and various plant-derived compounds to be used in combination therapy (Gupta et al., 2014). These inhibitors work by disrupting the energy supply of the pumps or by directly blocking the transport channel, thereby keeping the antibiotic inside the cell to reach its target. However, the development of clinical EPIs is challenged by the need for high specificity to avoid inhibiting essential human transporters like P-glycoprotein.

Other names

Mtb multidrug efflux pumpsMycobacterial efflux systemsMtb transportersMtb drug efflux systems

Efflux pump inhibitors (EPIs) function by either depleting the energy sources required for active transport (such as the proton motive force or ATP hydrolysis), competitively inhibiting the substrate-binding pocket of the pump, or physically blocking the exit channel to prevent the extrusion of antibiotic molecules (Sharma et al., 2019; Remm et al., 2022).