Adzah, Benedicta Yayra, Biniyam, Prince Danan, Ohene-Adu, Victoria, Osei, Michael, Adu-Adje, Kwabena, Elmes, Victoria, Goodall, Iain, Faustina, Vuvor, Agboyibor, Yvonne Dogbeda, Gyan, Patrick, Quansah, Paul, Amengor, Cyril Makafui, Boateng, Joshua ORCID: https://orcid.org/0000-0002-6310-729X, Zhang, En, Ampomah-Wireko, Maxwell, Oyeh, Ernest and Amengor, Cedric Dzidzor Kodjo (2026) Dual-targeting Sulfamethoxazole derivatives overcome multidrug resistance in ESKAPE pathogens by inhibiting quorum sensing and efflux pumps. RSC Advances. ISSN 2046-2069 (Online) (In Press)

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Abstract

The rapid emergence of pan-drug-resistant pathogens necessitates innovative antimicrobial strategies that overcome conventional resistance. This study reports the structure-guided design of sulfamethoxazole derivatives as dual inhibitors of quorum sensing (LasR) and efflux pumps (AcrB), alongside the classic dihydropteroate synthase (DHPS) target. High-throughput virtual screening of 54 derivatives, followed by MM-GBSA analysis, prioritized five novel compounds for synthesis. Their structures were confirmed by ¹H/¹³C NMR, FT-IR, and mass spectrometry. All compounds demonstrated potent growth inhibition (MICs 15.625–125 µg/mL) against Proteus mirabilis, Salmonella typhi, and Escherichia coli, though activity against the more resistant Pseudomonas aeruginosa was reduced. Critically, lead compounds SMX033 and SMX015 achieved >99% biofilm inhibition against P. mirabilis, and SMX033 showed significant efflux pump inhibition, directly validating our in silico predictions of a multi-target mechanism. In particular, compound SMX 033 exhibited the best antimicrobial activity and lowest cytotoxicity of all the sulfamethoxazole derivatives with a CCC50 value of 286.20 μM against Vero cells. Despite predicted in silico genotoxicity, these derivatives provide a promising chemical scaffold for combating multidrug-resistant infections by concurrently attenuating virulence and restoring antibiotic susceptibility.

Item Type:	Article
Uncontrolled Keywords:	Sulfamethoxazole derivatives, antimicrobial resistance, ESKAPE pathogens
Subjects:	Q Science > Q Science (General) R Medicine > R Medicine (General) T Technology > T Technology (General)
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	06 Feb 2026 11:08
URI:	https://gala.gre.ac.uk/id/eprint/52408

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