![\"\"](\"https:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Nunes.jpg\")
<\/figure>PE4 – B\u00e1rbara<\/strong> Nunes <\/strong><\/p>\n\n\n\n LEPABE, ALiCE, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s\/n, 4200-465 Porto, Portugal<\/p>\n\n\n\n e-mail<\/a> – LinkedIn<\/a><\/strong> –<\/strong> ORCID<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" PE4 – B\u00e1rbara Nunes LEPABE, ALiCE, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s\/n, 4200-465 Porto, Portugal e-mail – LinkedIn – ORCID Quaternary ammonium and phosphonium salts as antimicrobial agents: synthesis, biological evaluation, […]<\/p>\n","protected":false},"author":9643,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1892","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1892","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/9643"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=1892"}],"version-history":[{"count":1,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1892\/revisions"}],"predecessor-version":[{"id":1894,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1892\/revisions\/1894"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=1892"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=1892"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=1892"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Quaternary ammonium and phosphonium salts as antimicrobial agents: synthesis, biological evaluation, and mechanistic insights<\/strong><\/td><\/tr> Nunes B\u00e1rbara1<\/sup>, Cagide Fernando 2<\/sup>, Borges Fernanda 2,3<\/sup>, and Sim\u00f5es Manuel 1<\/sup>
<\/em>
1<\/em><\/sup> LEPABE, ALiCE, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s\/n, 4200-465 Porto, Portugal; up201804372@edu.fe.up.pt;
2<\/sup> MedInUP\/RISE-Health Department of Biomedicine \u2013 Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
3<\/em><\/sup> Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s\/n, 4169-007 Porto, Portugal.<\/td><\/tr>Abstract<\/strong>
The rapid emergence of antimicrobial resistance (AMR), particularly among multidrug-resistant (MDR) ESKAPEE pathogens, necessitates antibacterial agents with fundamentally new mechanisms of action. Quaternary heteronium salts (QHSs), encompassing ammonium and phosphonium derivatives, have emerged as versatile amphiphilic scaffolds with significant antibacterial potential. Here, we report a systematic medicinal chemistry study integrating rational design, structure\u2013activity relationship (SAR) analysis, and detailed mechanistic investigation. A focused library of 49 compounds, spanning seven cationic headgroups (triphenylphosphonium (TPP\u207a), methylimidazolium, isoquinolinium, quinolinium, methylpyridinium, pyridinium, and triethylammonium) and alkyl chains (C6<\/sub>\u2013C18<\/sub>), was synthesized and evaluated against Staphylococcus aureus<\/em>, including resistant strains. Antibacterial activity was strongly governed by both the cationic core and lipophilicity, with C14<\/sub> derivatives consistently exhibiting optimal potency. TPP\u207a and methylimidazolium analogues emerged as the most active, albeit with increased cytotoxicity in HepG2 cells [1]. Broad-spectrum screening through CO-ADD identified 33 active compounds, predominantly against Gram-positive bacteria and Candida albicans<\/em>, whereas Gram-negative activity remained limited, consistent with permeability barriers. Toxicological profiling (HEK-293 and hemolysis) revealed a clear chain length\u2013dependent increase in cytotoxicity [2]. Mechanistic studies of the most potent C14<\/sub> derivatives in S. aureus<\/em> demonstrated pronounced, structure-dependent disruption of the bacterial envelope [3]. To improve the therapeutic window, para<\/em>-substituted TPP\u207a derivatives bearing electron-donating and electron-withdrawing groups (OCH\u2083, F, CF\u2083) were synthesized. Notably, 4-CF\u2083 analogues retained potent antibacterial activity while exhibiting reduced cytotoxicity in NHDF and HepG2 cells. LC-MS\/MS confirmed intracellular accumulation, while Seahorse XF and DiOC\u2082(3) assays revealed bioenergetic impairment and membrane depolarization. Collectively, this work establishes optimized TPP\u207a-based QHSs as promising membrane-targeting antibacterial chemotypes with potential against resistant Gram-positive pathogens.<\/td><\/tr>References \u00a0<\/strong>
[1] Nunes, B.; Cagide, F.; Fernandes, C.; Borges, A.; Borges, F.; Sim\u00f5es, M. Efficacy of novel quaternary ammonium and phosphonium salts differing in cation type and alkyl chain length against antibiotic-resistant Staphylococcus aureus<\/em>. Int. J. Mol. Sci.<\/em> 2024<\/strong>, 25<\/em>, 504. https:\/\/doi.org\/10.3390\/ijms25010504
[2] Nunes, B.; Cagide, F.; Borges, F.; Sim\u00f5es, M. Antimicrobial activity and cytotoxicity of novel quaternary ammonium and phosphonium salts. J. Mol. Liq.<\/em> 2024<\/strong>, 401<\/em>, 124616. https:\/\/doi.org\/10.1016\/j.molliq.2024.124616
[3] Nunes, B.; Cagide, F.; Borges, A.; Borges, F.; Sim\u00f5es, M. Antibacterial effects of novel quaternary ammonium and phosphonium salts against Staphylococcus aureus<\/em>. J. Appl. Microbiol.<\/em> 2025<\/strong>, 136<\/em>, lxaf122. https:\/\/doi.org\/10.1093\/jambio\/lxaf122<\/a><\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n\n\n\n