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Adv."],"published-print":{"date-parts":[[2026,3,20]]},"abstract":"<jats:p>\n                    We are in dire need of antibiotics endowed with new mechanisms of action. The DksA protein regulates the transcription of genes involved in metabolism, translation, and virulence in Gram-negative bacteria. DksA is evolutionarily conserved among Gram-negative pathogens but is absent in humans. Here, we identified a conserved acidic pocket at the tip of the coiled-coil domain of DksA that is amenable for drug development. Our bioinformatics and experimental approaches identified\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide as a DksA inhibitor with moderate antimicrobial activity. Derivatization of the dimethoxyphenyl functionality and aliphatic linker of\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide generated several new chemical entities with excellent IC\n                    <jats:sub>50<\/jats:sub>\n                    values against DksA-regulated in vitro transcription and improved antimicrobial activity against\n                    <jats:italic toggle=\"yes\">Salmonella<\/jats:italic>\n                    and several other Gram-negative bacteria. Our pharmacokinetic and pharmacodynamic evaluations indicate that the\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -(4-phenylbutyl)-1H-1,2,4-triazole-3-carboxamide analog is absorbed in the gastrointestinal tract of rats and is distributed into viscera. The systemic administration of the\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -(4-phenylbutyl)-1H-1,2,4-triazole-3-carboxamide analog protected mice against oral and systemic\n                    <jats:italic toggle=\"yes\">Salmonella<\/jats:italic>\n                    infections while practically preventing the formation of microabscesses and necrotic foci in\n                    <jats:italic toggle=\"yes\">Salmonella<\/jats:italic>\n                    -infected mice. Our investigations have identified a previously unknown class of antibiotics against the transcriptional regulator DksA that is endowed with antimicrobial activity against Gram-negative pathogens.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea6832","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T17:59:43Z","timestamp":1773856783000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["DksA inhibitors against intracellular and persistent\n                    <i>Salmonella<\/i>\n                    are effective in acute models of infection"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4932-4490","authenticated-orcid":true,"given":"Ju-Sim","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA."},{"name":"Cogent Biosciences, 4840 Pearl E. Circle, Boulder, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu J.","family":"Choi","sequence":"additional","affiliation":[{"name":"University of Colorado Cancer Center, University of Colorado, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2086-9911","authenticated-orcid":true,"given":"Simona","family":"Senovaityte","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"McCollister","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8549-4369","authenticated-orcid":true,"given":"Nathan","family":"Wlodarchak","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA."},{"name":"Veterans Affairs Eastern Colorado Health Care System, Denver, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-1400","authenticated-orcid":true,"given":"David J.","family":"Orlicky","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0707-0138","authenticated-orcid":true,"given":"Peter J.","family":"Rice","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4760-2773","authenticated-orcid":true,"given":"Shaodong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA."},{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8157-5281","authenticated-orcid":true,"given":"Michael F.","family":"Wempe","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA."},{"name":"University of Colorado Cancer Center, University of Colorado, Aurora, CO, USA."},{"name":"Department of Biologics and Physical Sciences, Kentucky State University, Frankfort, KY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6181-4185","authenticated-orcid":true,"given":"Andr\u00e9s","family":"V\u00e1zquez-Torres","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA."},{"name":"Veterans Affairs Eastern Colorado Health Care System, Denver, CO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"Antimicrobial Resistance: Global Report on Surveillance (World Health Organization 2014)."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00030-10"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.15190\/d.2019.15"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00674-6"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky019"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag0822"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2008.11.005"},{"key":"e_1_3_2_9_2","first-page":"1","article-title":"Antimicrobial resistance: Tackling a crisis for the health and wealth of nations","volume":"20","author":"O\u2019Neill J.","year":"2014","unstructured":"J. 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