Efflux Pump Inhibitors and the Future of Antimicrobial Therapy

We are in a post-antibiotic era where once treatable bacterial infections are a renewed and serious threat to public health. This is largely driven by the overuse and misuse of antibiotics which is accelerating the emergence of multidrug-resistant (MDR), extensively drug-resistant
(XDR) and pan drug-resistant (PDR) pathogens. One of the key resistance mechanisms in these organisms like Acinetobacter baumannii is the use of efflux pumps. These membrane proteins help bacteria survive by expelling a wide variety of antimicrobial compounds, which lowers intracellular drug concentrations. With slow antibiotic development, Efflux Pump Inhibitors (EPIs) have emerged as a solution to re-estabilish the activity of current antibiotics. EPIs work through different mechanisms: direct inhibition of pump activity, disruption of energy sources like the proton motive force, suppression of gene expression and interference with pump structure. Sources of EPIs are plant derived compounds (e.g. alkaloids like reserpine),
microbial metabolites and synthetic molecules. EPIs are a cost effective and innovative adjunct to antimicrobial therapy which can reverse bacterial resistance, increase the antibiotic potency and inhibit efflux induced biofilm formation. While there are challenges like limited cell permeability, toxicity concerns and lack of clinical data. Development of EPIs is essential to preserve the utility of current antibiotics especially against high priority ESKAPE pathogens.

KEYWORDS: Antibiotic Resistance, Efflux Pumps (EPs), Efflux Pump Inhibitors (EPIs), Multidrug Resistance (MDR), Bacterial Resistance Mechanisms, Acinetobacter baumannii, Carbapenem-Resistant A. baumannii (CRAB), Efflux Pump Classification, ResistanceNodulation-Cell Division (RND) transporters, ATP-Binding Cassette (ABC) transporters, Major Facilitator Superfamily (MFS) transporters, Proton Motive Force (PMF), Mechanisms
of EPIs, Naturally Derived EPIs, Synthetically Derived EPIs, Therapeutic Uses of EPIs, ESKAPE Pathogens, Biofilm Formation.