{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:45:45Z","timestamp":1792784745631,"version":"4.5.0"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"Project Grant from the Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"},{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/na","name":"Tier 1 Canada Research Chair award","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Antibiotic resistance in Gram-negative bacteria is a major global health threat, in part because of the permeability barriers of their double-membrane envelope and active efflux systems. While porins, lipopolysaccharides, and efflux pumps have been extensively studied, the role of membrane energetics, particularly the Donnan potential (DP), in antibiotic susceptibility remains poorly understood. The DP arises from negatively charged osmoregulated periplasmic glucans (OPGs), which generate an electrostatic potential in the periplasm that is capable of influencing how molecules traverse the outer membrane. Here, we systematically examine how OPG-dependent electrostatic changes associated with the DP shape antibiotic susceptibility in Escherichia coli. By altering the environmental osmolarity, we generated conditions that changed OPG abundance and were expected to alter associated periplasmic electrostatics, revealing that low-salt conditions enhance the potency of cationic antibiotics but reduce the activity of anionic compounds, whereas high-salt conditions or OPG deficiency attenuate cationic drug activity. Strains producing neutral OPGs phenocopied OPG-deficient mutants, implying that the OPG charge is involved in this effect. Clinical E. coli isolates varied in sensitivity to osmolarity- and OPG-dependent electrostatic effects, and similar trends were observed across multiple Gram-negative pathogens. Finally, we show that dietary salt intake modulates antibiotic efficacy in vivo in a manner consistent with the salt-dependent susceptibility observed in vitro. Together, these findings systematically quantify antibiotic susceptibility phenotypes across a broad compound panel and under environmental and genetic perturbations expected to alter OPG-associated periplasmic electrostatics and suggest new principles for antibiotic design and therapeutic optimization against multidrug-resistant pathogens.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00581","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:01:47Z","timestamp":1790604107000},"page":"3502-3513","source":"Crossref","is-referenced-by-count":0,"title":["Electrostatic\nModulation of Antibiotic Susceptibility\nby the Bacterial Donnan Potential"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-7377","authenticated-orcid":true,"given":"Maya A.","family":"Farha","sequence":"first","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7405-0500","authenticated-orcid":true,"given":"Megan M.","family":"Tu","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodion","family":"Gordzevich","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Rachwalski","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-8112","authenticated-orcid":true,"given":"Eric D.","family":"Brown","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"2026100909100623600_cit1","volume-title":"Antimicrobial\nResistance: Tackling a Crisis for the Health and Wealth of Nations","author":"O\u2019Neill","year":"2014"},{"issue":"7586","key":"2026100909100623600_cit2","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nature17042","article-title":"Antibacterial drug discovery in the\nresistance era","volume":"529","author":"Brown","year":"2016","journal-title":"Nature"},{"issue":"6","key":"2026100909100623600_cit3","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.83","article-title":"Roadmap for antibiotic\ndiscovery","volume":"1","author":"Shore","year":"2016","journal-title":"Nat. Microbiol."},{"key":"2026100909100623600_cit4","volume-title":"Global Priority List of Antibiotic-Resistant\nBacteria to Guide Research,\nDiscovery, and Development of New Antibiotics","author":"World Health Organization.","year":"2017"},{"issue":"4","key":"2026100909100623600_cit5","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1128\/MMBR.67.4.593-656.2003","article-title":"Molecular\nbasis of bacterial outer membrane permeability revisited","volume":"67","author":"Nikaido","year":"2003","journal-title":"Microbiol. Mol. Biol. Rev."},{"issue":"1","key":"2026100909100623600_cit6","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/nyas.14134","article-title":"Permeability barriers\nof Gram-negative pathogens","volume":"1459","author":"Zgurskaya","year":"2020","journal-title":"Ann. N.Y. Acad.\nSci."},{"issue":"10","key":"2026100909100623600_cit7","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.1021\/jm700967e","article-title":"Physicochemical properties of antibacterial compounds:\nImplications for drug discovery","volume":"51","author":"O\u2019Shea","year":"2008","journal-title":"J. Med. Chem."},{"issue":"7654","key":"2026100909100623600_cit8","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/nature22308","article-title":"Predictive compound accumulation\nrules yield a broad-spectrum antibiotic","volume":"545","author":"Richter","year":"2017","journal-title":"Nature"},{"issue":"11","key":"2026100909100623600_cit9","doi-asserted-by":"publisher","first-page":"2535","DOI":"10.1021\/cb5003015","article-title":"General\nplatform for systematic quantitative\nevaluation of small-molecule permeability in bacteria","volume":"9","author":"Davis","year":"2014","journal-title":"ACS Chem. Biol."},{"issue":"1","key":"2026100909100623600_cit10","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1021\/acsinfecdis.0c00715","article-title":"Compound\nuptake into Escherichia coli can be\nfacilitated by N-alkyl guanidiniums and pyridiniums","volume":"7","author":"Perlmutter","year":"2021","journal-title":"ACS Infect. Dis."},{"issue":"6","key":"2026100909100623600_cit11","doi-asserted-by":"publisher","first-page":"2532","DOI":"10.1021\/jm201275d","article-title":"Molecular\ndeterminants of AcrB-mediated bacterial efflux implications for drug\ndiscovery","volume":"55","author":"Manchester","year":"2012","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026100909100623600_cit12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08747-8","article-title":"Molecular\nrationale behind the differential substrate specificity of bacterial\nRND multi-drug transporters","volume":"7","author":"Ramaswamy","year":"2017","journal-title":"Sci. Rep."},{"issue":"4","key":"2026100909100623600_cit13","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01925-20","article-title":"Physicochemical and structural parameters contributing\nto the antibacterial activity and efflux susceptibility of small-molecule\ninhibitors of Escherichia coli","volume":"65","author":"El Zahed","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"issue":"4","key":"2026100909100623600_cit14","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.tim.2019.12.008","article-title":"The microbiologist\u2019s guide\nto membrane potential\ndynamics","volume":"28","author":"Benarroch","year":"2020","journal-title":"Trends Microbiol."},{"issue":"7346","key":"2026100909100623600_cit15","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nature10069","article-title":"Metabolite-enabled eradication of\nbacterial persisters by aminoglycosides","volume":"473","author":"Allison","year":"2011","journal-title":"Nature"},{"issue":"1","key":"2026100909100623600_cit16","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1080\/22221751.2020.1740611","article-title":"L-Lysine potentiates\naminoglycosides against Acinetobacter baumannii via\nregulation of proton motive force and antibiotics uptake","volume":"9","author":"Deng","year":"2020","journal-title":"Emerg. Microbes Infect."},{"issue":"3","key":"2026100909100623600_cit17","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1021\/acsinfecdis.7b00194","article-title":"Bicarbonate alters\nbacterial susceptibility to antibiotics by targeting the proton motive\nforce","volume":"4","author":"Farha","year":"2018","journal-title":"ACS Infect. Dis."},{"issue":"3","key":"2026100909100623600_cit18","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/S0021-9258(19)57283-0","article-title":"Porin channels\nin intact cells of Escherichia coli are not affected by Donnan potentials\nacross the outer membrane","volume":"263","author":"Sen","year":"1988","journal-title":"J. Biol. Chem."},{"issue":"21","key":"2026100909100623600_cit19","doi-asserted-by":"publisher","first-page":"7850","DOI":"10.1016\/S0021-9258(17)41044-1","article-title":"Periplasmic space in Salmonella typhimurium and Escherichia coli","volume":"252","author":"Stock","year":"1977","journal-title":"J. Biol. Chem."},{"key":"2026100909100623600_cit20","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/S0096-4174(18)30049-0","article-title":"Transport\nprocesses in ionic membranes","volume":"3","author":"Teorell","year":"1953","journal-title":"Prog. Biophys.\nBiophys. Chem."},{"key":"2026100909100623600_cit21","doi-asserted-by":"crossref","unstructured":"Bontemps-Gallo, S.; Bohin, J. P.; Lacroix, J. M.\n          Osmoregulated\nperiplasmic glucans\n          EcoSal Plus\n          2017; Vol. 7(2), 10.1128\/ecosalplus.esp-0001-2017.","DOI":"10.1128\/ecosalplus.esp-0001-2017"},{"issue":"4733","key":"2026100909100623600_cit22","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1126\/science.3941890","article-title":"Osmotic adaptation\nby Gram-negative\nbacteria: Possible role for periplasmic oligosaccharides","volume":"231","author":"Miller","year":"1986","journal-title":"Science"},{"issue":"14","key":"2026100909100623600_cit23","doi-asserted-by":"publisher","first-page":"4208","DOI":"10.1016\/S0021-9258(17)33282-9","article-title":"Identification\nof sn-glycero-1-phosphate and phosphoethanolamine residues linked\nto the membrane-derived oligosaccharides of Escherichia coli","volume":"251","author":"Kennedy","year":"1976","journal-title":"J. Biol. Chem."},{"issue":"5","key":"2026100909100623600_cit24","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1073\/pnas.70.5.1368","article-title":"Metabolism\nof membrane phospholipids and its relation to a novel\nclass of oligosaccharides in Escherichia coli","volume":"70","author":"Golde","year":"1973","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"20","key":"2026100909100623600_cit25","doi-asserted-by":"publisher","first-page":"10135","DOI":"10.1016\/S0021-9258(19)86683-8","article-title":"Structural studies\nof the membrane-derived oligosaccharides of Escherichia coli","volume":"254","author":"Schneider","year":"1979","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026100909100623600_cit26","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1574-6968.2000.tb09075.x","article-title":"Osmoregulated\nperiplasmic glucans in Proteobacteria","volume":"186","author":"Bohin","year":"2000","journal-title":"FEMS\nMicrobiol. Lett."},{"issue":"4","key":"2026100909100623600_cit27","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1073\/pnas.79.4.1092","article-title":"Osmotic\nregulation and the biosynthesis of membrane-derived oligosaccharides\nin Escherichia coli","volume":"79","author":"Kennedy","year":"1982","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"2","key":"2026100909100623600_cit28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1159\/000168062","article-title":"Urine electrolytes\nand osmolality: When and how to use them","volume":"10","author":"Kamel","year":"1990","journal-title":"Am.\nJ. Nephrol."},{"issue":"10","key":"2026100909100623600_cit29","doi-asserted-by":"publisher","first-page":"2588","DOI":"10.1172\/JCI119802","article-title":"Ion composition\nof airway surface liquid of patients with cystic fibrosis as compared\nwith normal and disease-control subjects","volume":"100","author":"Knowles","year":"1997","journal-title":"J.\nClin. Invest."},{"issue":"2","key":"2026100909100623600_cit30","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/0022-2836(91)90212-O","article-title":"Characterization of the cytoplasm\nof Escherichia coli K-12 as a function\nof external osmolarity: Implications for protein-DNA\ninteractions in vivo","volume":"222","author":"Cayley","year":"1991","journal-title":"J. Mol. Biol."},{"issue":"9","key":"2026100909100623600_cit31","doi-asserted-by":"publisher","first-page":"3685","DOI":"10.1016\/S0021-9258(18)97200-5","article-title":"The release\nof enzymes from Escherichia coli by osmotic shock and during the formation of\nspheroplasts","volume":"240","author":"Neu","year":"1965","journal-title":"J. Biol. Chem."},{"key":"2026100909100623600_cit32","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6750-13-18","article-title":"High level\nproduction of tyrosinase in recombinant Escherichia coli","volume":"13","author":"Ren","year":"2013","journal-title":"BMC Biotechnol."},{"issue":"1","key":"2026100909100623600_cit33","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0378-1097(03)00323-9","article-title":"Membrane-derived oligosaccharides\n(MDOs) are essential for sodium dodecyl sulfate resistance in Escherichia coli","volume":"223","author":"Rajagopal","year":"2003","journal-title":"FEMS Microbiol.\nLett."},{"issue":"22","key":"2026100909100623600_cit34","doi-asserted-by":"publisher","first-page":"6905","DOI":"10.1113\/JP274927","article-title":"Dietary sodium induces a redistribution\nof the tubular\nmetabolic workload","volume":"595","author":"Udwan","year":"2017","journal-title":"J. Physiol."},{"issue":"6","key":"2026100909100623600_cit35","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics10060701","article-title":"Donnan potential\nacross the outer membrane of Gram-negative bacteria and its effect\non the permeability of antibiotics","volume":"10","author":"Alegun","year":"2021","journal-title":"Antibiotics"},{"issue":"38","key":"2026100909100623600_cit36","doi-asserted-by":"publisher","first-page":"26464","DOI":"10.1074\/jbc.M114.585869","article-title":"High salt concentrations increase permeability through\nOmpC channels of Escherichia coli","volume":"289","author":"Kojima","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2026100909100623600_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2024.102562","article-title":"Important\nchallenges to finding new\nleads for new antibiotics","volume":"83","author":"Farha","year":"2025","journal-title":"Curr. Opin. Microbiol."},{"issue":"3","key":"2026100909100623600_cit38","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1021\/ac60111a017","article-title":"Colorimetric\nmethod for determination of sugars and related substances","volume":"28","author":"DuBois","year":"1956","journal-title":"Anal. Chem."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00581","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/10\/3502\/68677678\/acsinfecdis.6c00581.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/10\/3502\/68677678\/acsinfecdis.6c00581.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:18:44Z","timestamp":1791551924000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/10\/3502\/5440026\/Electrostatic-Modulation-of-Antibiotic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,28]]},"published-print":{"date-parts":[[2026,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00581","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}