{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:54:59Z","timestamp":1791554099406,"version":"4.3.4"},"reference-count":59,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1AI167284"],"award-info":[{"award-number":["RO1AI167284"]}],"id":[{"id":"10.13039\/100000002","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>Current treatment options for multidrug-resistant (MDR) Gram-negative infections are effectively limited to last-resort antibiotics, such as the polymyxins. Clinical use of polymyxins remains limited due to significant nephrotoxic side effects, and is further limited as a result of increasing polymyxin resistance. The novel polymyxin antibiotic, SPR206, developed in 2019, retains potency against polymyxin-susceptible Gram-negative bacteria while showing no adverse side effects in Phase 1 clinical trials. However, resistance to SPR206 is anticipated through the same mechanisms that drive resistance to the currently available polymyxins. We have reported several small-molecule polymyxin adjuvant scaffolds that reverse resistance in polymyxin-resistant Gram-negative bacteria. Herein, we describe the evaluation of six previously reported colistin adjuvants for the modulation of SPR206 activity in polymyxin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. Several adjuvants exhibit equipotent or increased activity with SPR206 compared to that with colistin, and maintain SPR206 adjuvant activity against a panel of clinical isolates. Additionally, bacteria do not evolve resistance to the combination of adjuvant NDM-27 and SPR206 over a seven-day period, with low spontaneous mutation frequencies of 4.54 \u00d7 10\u20138 (AB4106) and 3.32 \u00d7 10\u20139 (KPB9) at 4X the SPR206 minimum inhibitory concentration. Overall, these data support the potential use of previously developed adjuvants to augment the activity of next-generation polymyxins.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00742","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:11Z","timestamp":1789632191000},"page":"3559-3568","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the\nUtility of Colistin Adjuvants To Encompass\nNext-Generation Polymyxins against Polymyxin-Resistant\n                    <i>Acinetobacter baumannii<\/i>\n                    and\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1021","volume":"12","author":[{"given":"Ansley M.","family":"Nemeth","sequence":"first","affiliation":[{"name":"University of Notre Dame , , , ,","place":["Notre Dame, Indiana, United States, 46556"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Stefaniak","sequence":"additional","affiliation":[{"name":"University of Notre Dame , , , ,","place":["Notre Dame, Indiana, United States, 46556"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley N.","family":"Crotteau","sequence":"additional","affiliation":[{"name":"University of Notre Dame , , , ,","place":["Notre Dame, Indiana, United States, 46556"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine , , , ,","place":["Pittsburgh, Pennsylvania, United States, 15261"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Ernst","sequence":"additional","affiliation":[{"name":"University of Maryland School of Dentistry , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta J.","family":"Melander","sequence":"additional","affiliation":[{"name":"University of Notre Dame , , , ,","place":["Notre Dame, Indiana, United States, 46556"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8271-4696","authenticated-orcid":true,"given":"Christian","family":"Melander","sequence":"additional","affiliation":[{"name":"University of Notre Dame , , , ,","place":["Notre Dame, Indiana, United States, 46556"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"issue":"4","key":"2026100909103469700_cit1","first-page":"277","article-title":"The Antibiotic\nResistance Crisis Part 1: Causes and Threats","volume":"40","author":"Ventola","year":"2015","journal-title":"P T"},{"key":"2026100909103469700_cit2","doi-asserted-by":"publisher","first-page":"j4339","DOI":"10.1136\/bmj.j4339","article-title":"Few Novel\nAntibiotics in the Pipeline, WHO Warns","volume":"358","author":"Kmietowicz","year":"2017","journal-title":"BMJ."},{"key":"2026100909103469700_cit3","volume-title":"Antimicrobial\nResistance: Tackling a Crisis for the Health and Wealth of Nations","author":"O\u2019Neill","year":"2014"},{"key":"2026100909103469700_cit4","unstructured":"World Health Organization.\n          \n          Antimicrobial Resistance - Global Report\non Surveillance, 2014."},{"key":"2026100909103469700_cit5","unstructured":"The World Bank Group.\n          \n          Drug-Resistant Infections: A Threat to our\nEconomic Future; The World Bank: Washington, D.C, 2017."},{"key":"2026100909103469700_cit6","doi-asserted-by":"publisher","first-page":"25","DOI":"10.4137\/PMC.S14459","article-title":"Antibiotics and bacterial\nresistance in the 21st century","volume":"6","author":"Fair","year":"2014","journal-title":"Perspect Medicin\nChem."},{"key":"2026100909103469700_cit7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-981-99-8799-3_1","article-title":"Medical Importance of ESKAPE\nPathogens","volume-title":"ESKAPE Pathogens: Detection,\nMechanisms and Treatment Strategies","author":"Salim","year":"2024"},{"key":"2026100909103469700_cit8","volume-title":"WHO Bacterial Priority\nPathogens List","author":"Sati","year":"2024"},{"key":"2026100909103469700_cit9","volume-title":"WHO Priority Pathogens List for R&D of\nNew Antibiotics","author":"World Heath Organization.","year":"2017"},{"issue":"1","key":"2026100909103469700_cit10","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.chempr.2017.06.014","article-title":"Reaction: Broad-Spectrum Antibiotics, a Call for Chemists","volume":"3","author":"Richter","year":"2017","journal-title":"Chem"},{"issue":"4","key":"2026100909103469700_cit11","doi-asserted-by":"publisher","first-page":"772","DOI":"10.3390\/microorganisms12040772","article-title":"A Review on Colistin\nResistance: An Antibiotic of Last Resort","volume":"12","author":"Mondal","year":"2024","journal-title":"Microorganisms"},{"issue":"10","key":"2026100909103469700_cit12","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1021\/acsinfecdis.9b00217","article-title":"Design\nof Next Generation Polymyxins with Lower Toxicity:\nThe Discovery of SPR206","volume":"5","author":"Brown","year":"2019","journal-title":"ACS Infect. 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Dis."},{"issue":"3","key":"2026100909103469700_cit16","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.ijantimicag.2015.06.005","article-title":"Use of\ncolistin-containing products within the European Union and European\nEconomic Area (EU\/EEA): development of resistance in animals and possible\nimpact on human and animal health","volume":"46","author":"Catry","year":"2015","journal-title":"Int. J. Antimicrob.\nAgents"},{"issue":"2","key":"2026100909103469700_cit17","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1128\/cmr.00064-16","article-title":"Antibacterial\nActivity, Susceptibility\nTesting, and Resistance Mechanisms Encoded by Plasmids or Chromosomes","volume":"30","author":"Poirel","year":"2017","journal-title":"Clin. Microbiol. 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Biol."},{"issue":"25","key":"2026100909103469700_cit36","doi-asserted-by":"publisher","first-page":"3549","DOI":"10.1016\/j.tet.2015.09.019","article-title":"Second Generation\nModifiers of Colistin Resistance Show Enhanced Activity and Lower\nInherent Toxicity","volume":"72","author":"Brackett","year":"2016","journal-title":"Tetrahedron"},{"issue":"20","key":"2026100909103469700_cit37","doi-asserted-by":"publisher","first-page":"5749","DOI":"10.1016\/j.bmc.2017.08.055","article-title":"Small Molecule Adjuvants that Suppress\nBoth Chromosomal\nand mcr-1 Encoded Colistin-Resistance and Amplify\nColistin Efficacy in Polymyxin Susceptible Bacteria","volume":"25","author":"Barker","year":"2017","journal-title":"Bioorg. Med. 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Ph.D. Thesis; University of Notre Dame: United\nStates\u2500Indiana, 2024. https:\/\/www.proquest.com\/dissertations-theses\/investigation-small-molecule-adjuvants-that\/docview\/3150190208\/se-2."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00742","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/10\/3559\/68540186\/acsinfecdis.6c00742.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/10\/3559\/68540186\/acsinfecdis.6c00742.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:43:07Z","timestamp":1791553387000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/10\/3559\/5431810\/Expanding-the-Utility-of-Colistin-Adjuvants-To"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":59,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,17]]},"published-print":{"date-parts":[[2026,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00742","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}