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… This crystallographic insight demonstrated specific interactions between the inhibitor and critical proton-relaying residues, including aspartates essential for harnessing the proton motive force, thereby impeding the energy transduction necessary for pump operation (Plé et al., 2022).

… Additionally, competitive EPIs typically failed to disrupt the energetic coupling between efflux activity and the proton motive force (PMF), allowing bacteria to maintain efflux competence through metabolic adaptation or compensatory upregulation of alternative transporters (Nishino et al., 2021; Rouvier et al., 2025). Collectively, these shortcomings highlighted the need …

… Carbonyl cyanide-m-chlorophenylhydrazone (CCCP) is an EPI ionophore that disrupts the proton motive force (PMF) by affecting both its components, Δψ and ΔpH (Bhattacharyya et al., 2017). Verapamil is a small molecule that acts as an ion channel blocker and is used in the treatment of hypertension …

Accordingly, the development of efflux pump inhibitors that simultaneously disrupt drug export and proton motive force utilization represents a promising strategy for restoring antibiotic efficacy against MDR Gram-negative pathogens (Gaurav et al., 2023; Kumawat et al., 2023). The objective of this review is to provide a comprehensive …

… Antibiotic accumulation inside the bacterial cells can disrupt the Proton Motive Force (PMF) by increasing proton concentration inside the cell. After the accumulation of antibiotics, protons started to accumulate in the inner membrane of the bacteria, leads to directly damage the cytoplasmic membrane or indirectly affect components of …

Several recent investigations highlight the translational promise of both allosteric inhibitors and proton-motive-force (PMF)-targeting agents for combating antimicrobial-resistant infections in-vivo. These findings are primarily derived from well-established animal models, including murine systemic infection models, pulmonary infection models, and MRSA infection models, which …

… This blockage abrogates the Proton Motive Force (PMF)-driven functional rotation that effectively “freezing” the pump and halting drug extrusion (Wang et al., 2017; Plé et al., 2022). Molecular dynamics simulations also focus on inhibitors-based restriction of transmembrane helices flexibility, preventing the remodeling of the drug-binding …

… The protonated piperazine moiety of BDM88855 forms critical interactions with catalytic residues within the pump, blocking the proton motive force essential for transport and disrupting the functional rotation mechanism (Table 2; Plé et al., 2022). Besides pyridylpiperazines, other allosteric EPIs have been identified, including arylpiperazines like NMP (1 …

The efficiency of bacterial efflux pumps is closely linked to the energetic state of the cell, particularly the membrane potential (ΔΨ) component of the proton motive force (PMF), which drives proton-dependent transport systems, including the RND, MFS, and MATE pump families. Perturbation of ΔΨ reduces the energetic …

… These structural insights have established that binding of allosteric inhibitors at these sites modulates the conformational dynamics essential for pump function, disrupting proton motive force coupling and substrate transport without directly competing with antibiotics at the active site (Plé et al., 2022; Roy et al., 2024). Plé et …

… Among these systems, proton-motive force (PMF) dependent Resistance, Nodulation–Division (RND) efflux pumps, such as AcrAB-TolC, play a central role in both intrinsic and acquired antibiotic resistance by expelling structurally diverse antimicrobial agents. Recent evidence indicates that efflux pumps are not merely drug extrusion devices but …

… Efflux pumps harness the proton motive force (PMF), an electrochemical gradient across the inner membrane, as the primary energy source for substrate extrusion. Disruption or alteration of this membrane potential directly affects pump activity and efficiency (Whittle et al., 2024). Genetic knockout or functional inactivation of efflux pumps …

… Changes in environmental pH can significantly modulate the proton motive force (PMF), depends on the membrane potential (ΔΨ) and the transmembrane proton gradient (ΔpH), both of which drive the catalytic cycle of proton-dependent efflux pumps such as AcrAB–TolC. Changes in extracellular or cytoplasmic pH may therefore …

… Nodulation–Division (RND) family efflux pumps, such as AcrAB–TolC in Escherichia coli and Salmonella spp., which are powered by the proton motive force (PMF) across the inner membrane, are tripartite complexes that span the Gram-negative cell envelope to actively expel toxic compounds including antibiotics (Gaurav et …

… The RND family, primarily found in Gram-negative bacteria, includes tripartite assemblies such as AcrAB-TolC, which expel a wide range of antibiotics and toxic compounds using the proton motive force for energy (Chetri, 2023; Duffey et al., 2024). The MFS pumps are ubiquitous across bacterial species, functioning …

The catalytic cycles of multidrug efflux pumps, especially those in the RND and MFS families, are tightly coupled to the proton motive force (PMF) across the bacterial cytoplasmic membrane (Chetri, 2023; Li et al., 2024). This energy is transduced by dedicated proton relay networks within the inner membrane …

… Each AcrB protomer consists of three domains—the transmembrane domain (TMD), which harnesses the proton motive force to energize transport, the porter domain (PD) responsible for substrate recognition and binding, and the funnel domain (FD) that interfaces with AcrA (Vargiu et al., 2022). The pump operates through a …