With the advancement of antibiotics and chemotherapy drugs, their widespread use in clinical settings has led to the emergence of drug resistance in bacteria and tumor cells. One of the primary mechanisms of resistance is active efflux, where overexpression of efflux pumps expels drugs from the cell, reducing intracellular drug concentration and decreasing treatment effectiveness. Efflux pump inhibitors (EPIs) can counteract this by blocking the efflux process, restoring drug sensitivity and improving therapeutic outcomes. Additionally, EPIs may enhance drug absorption and reduce liver and kidney clearance, making them valuable in drug development.
Efflux pumps are generally classified into two types: ATP-hydrolysis-driven and proton gradient-driven. ATP-hydrolysis-driven pumps, such as P-gp and MRP1, are targeted by EPIs that inhibit their activity by interfering with ATP-binding membrane glycoproteins. Over time, three generations of these inhibitors have emerged. First-generation EPIs like verapamil and cyclosporin A showed limited efficacy and significant side effects, restricting their clinical use. Second-generation inhibitors, such as PSC833 and VX-710, improved on these shortcomings, offering better potency and fewer adverse effects. Third-generation EPIs, including LY335979 and XR9576, demonstrate higher selectivity and fewer drug interactions, showing great promise for future applications.
In addition to synthetic compounds, natural products like green tea polyphenols and echinacea sesquiterpenoids have also been explored for their efflux-inhibiting properties. Surfactants, such as Tween 80 and cremophor EL, are another class of EPIs that alter the structure of P-gp, thereby inhibiting its function.
Research on proton gradient-driven efflux pumps has also advanced. Compounds like 5"-MHC and MC-207,110 have shown promising results in enhancing the efficacy of antimicrobial agents. These findings highlight the importance of efflux pump inhibition in overcoming drug resistance and improving treatment outcomes.
Overall, efflux pump inhibitors hold significant potential in modern medicine, not only in reversing drug resistance but also in enhancing drug bioavailability. As research continues, we can expect more effective and safer EPIs to emerge, offering new hope in the fight against resistant pathogens and cancers.
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