{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:21:30Z","timestamp":1789906890708,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that O-acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections caused by critical pathogens spreading worldwide, Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella pneumoniae. Starting from a hit compound endowed with a nanomolar dissociation constant, we have rationally designed and synthesized a series of derivatives to be tested against S. Typhimurium OASS isoenzymes, StOASS-A and StOASS-B. All acidic derivatives have shown good activities in the nanomolar range against both OASS isoforms in vitro. Minimal Inhibitory Concentrations (MICs) were then evaluated, as well as compounds\u2019 toxicity. The compounds endowed with good activity in vitro and low cytotoxicity have been challenged as a potential colistin adjuvant against pathogenic bacteria in vitro and the fractional inhibitory concentration (FIC) index has been calculated to define additive or synergistic effects. Finally, the target engagement inside the S. Typhimurium cells was confirmed by using a mutant strain in which the OASS enzymes were inactivated. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants.<\/jats:p>","DOI":"10.3390\/ph15060766","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T04:39:55Z","timestamp":1655786395000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibitors of O-Acetylserine Sulfhydrylase with a Cyclopropane-Carboxylic Acid Scaffold Are Effective Colistin Adjuvants in Gram Negative Bacteria"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-6966","authenticated-orcid":false,"given":"Giannamaria","family":"Annunziato","sequence":"first","affiliation":[{"name":"P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0211-5293","authenticated-orcid":false,"given":"Costanza","family":"Spadini","sequence":"additional","affiliation":[{"name":"Operative Unit of Animals Infectious Diseases, Department of Veterinary Science, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4615-6786","authenticated-orcid":false,"given":"Marialaura","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Franko","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9946-9524","authenticated-orcid":false,"given":"Marialaura","family":"Pavone","sequence":"additional","affiliation":[{"name":"P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Iannarelli","sequence":"additional","affiliation":[{"name":"Operative Unit of Animals Infectious Diseases, Department of Veterinary Science, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Bruno","sequence":"additional","affiliation":[{"name":"P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9190-3712","authenticated-orcid":false,"given":"Marco","family":"Pieroni","sequence":"additional","affiliation":[{"name":"P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6787-0594","authenticated-orcid":false,"given":"Stefano","family":"Bettati","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1936-9858","authenticated-orcid":false,"given":"Clotilde Silvia","family":"Cabassi","sequence":"additional","affiliation":[{"name":"Operative Unit of Animals Infectious Diseases, Department of Veterinary Science, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-0627","authenticated-orcid":false,"given":"Barbara","family":"Campanini","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Costantino","sequence":"additional","affiliation":[{"name":"P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fmicb.2010.00134","article-title":"A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future","volume":"1","author":"Aminov","year":"2010","journal-title":"Front. 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