Authors
Danxia Kong, Baoyan Liu, Xingchen Ding, Yong Wang
Published in
Frontiers in microbiology. Volume 17. Pages 1915579. Epub Sep 22, 2026.
Abstract
Multidrug-resistant (MDR) Gram-negative bacteria-particularly carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii-remain among the hardest infections to treat, and Resistance-Nodulation-Division (RND) efflux pumps are central to that resistance, making them a recurring target for antibiotic-adjuvant strategies. Natural products offer chemically diverse starting points for efflux-modulating adjuvants, but a fall in MIC is hard to attribute to pump inhibition: membrane permeabilisation, proton-motive-force (PMF) dissipation, efflux-gene downregulation, intrinsic antibacterial activity and general stress responses all give the same readout. We review natural product-derived and semisynthetic RND efflux pump inhibitor-like (EPI-like) candidates in Gram-negative bacteria, organising the evidence by target pump, potentiated antibiotic, proposed mechanism, strength of supporting data and translational feasibility. In place of chemical structures, candidates are read through mechanism-relevant structure-feature associations and the extent of pump-specific validation. Throughout, we separate three routinely conflated claims-antibiotic synergy, functional efflux modulation and direct target binding-and grade them with a pragmatic five-level scheme aimed at curbing over-reading of MIC-based synergy. One pattern dominates: synergy is reported widely, yet candidates reaching pump-associated validation are scarce, and higher-grade pump-dependent evidence remains concentrated on Escherichia coli AcrB. Camalexin is the clearest AcrB-dependent phenotype, but only provisionally-a Level 4a grade resting on a single unreplicated study-while plumbagin and nordihydroguaiaretic acid also reach provisional Level 4a because their potentiation and efflux phenotypes were AcrB-dependent and were not explained by outer-membrane permeabilisation. Direct target engagement remains unproven; the rare Level 4 cases beyond AcrB rely on a MexXY-OprM chemical probe or on expression change alone. Comparable pump-specific support for MexB, MexY and AdeB is largely absent. The proposed roadmap should therefore be viewed as an AcrB-anchored hypothesis that requires independent validation across these clinically important pumps. We propose a mechanism-informed structure-feature model and a staged validation roadmap coupling pump-specific strains, membrane and PMF controls, direct target engagement, feature-guided optimisation, cytotoxicity/PK assessment and in vivo infection models.
PMID:
42840960
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
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