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Baxter Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007491","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Oregon VPRI Undergraduate Fellowship"},{"name":"University of Oregon Mentored Research Program"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM155575"],"award-info":[{"award-number":["R35GM155575"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Appl Environ Microbiol"],"published-print":{"date-parts":[[2025,10,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Bacterial pathogens regularly encounter oxygen (O\n                      <jats:sub>2<\/jats:sub>\n                      ) limitation at sites of infection in the human body. Many pathogens exhibit antibiotic recalcitrance under low O\n                      <jats:sub>2<\/jats:sub>\n                      conditions, spotlighting the need for new therapeutics that are effective in O\n                      <jats:sub>2<\/jats:sub>\n                      -limited environments. We demonstrate that several classes of antibiotics display limited toxicity against hypoxic cultures of the opportunistic pathogen,\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      , where the pathogen exhibits antibiotic tolerance. In O\n                      <jats:sub>2<\/jats:sub>\n                      -limited host environments, many pathogens employ nitrate respiration, marking this anaerobic bacterial metabolism as an excellent drug target. Chlorate is a nitrate analog that hijacks nitrate respiration to kill\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      . Chlorate acts as a prodrug: nitrate reductase reduces chlorate, thereby forming the toxic oxidizing agent, chlorite. Chlorate treatment is most toxic to\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      under anoxia and displays limited-to-no toxicity under hypoxic or oxic conditions. Thus, neither chlorate nor antibiotics alone efficiently kill O\n                      <jats:sub>2<\/jats:sub>\n                      -limited\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      . Excitingly, combined chlorate-antibiotic treatment showed that chlorate addition potentiates all tested classes of antibiotics, often eradicating hypoxic\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      populations to below detection. Chlorate addition reduced the lethal dose of ceftazidime by &gt;100-fold, further highlighting chlorate\u2019s capacity to potentiate antibiotic treatment. Unlike chlorate, we found that most antibiotics do not synergize with different classes of drugs, except for colistin. Given that combination therapy is a promising strategy for combating antibiotic treatment failure, future studies should continue exploring chlorate\u2019s therapeutic potential, including examining the mechanisms of chlorate-antibiotic synergy. Our work points to the critical relationship between bacterial physiology and drug efficacy and highlights anaerobic metabolism as a promising drug target.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Many antibiotics are less effective at killing pathogens under oxygen (O\n                        <jats:sub>2<\/jats:sub>\n                        )-limited conditions. Pathogens frequently encounter O\n                        <jats:sub>2<\/jats:sub>\n                        limitation within host environments, which helps explain why antibiotic therapies often fail to resolve chronic infections. We are investigating the relationship between O\n                        <jats:sub>2<\/jats:sub>\n                        availability and drug efficacy in the opportunistic pathogen,\n                        <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                        . In agreement with prior work, we demonstrate that\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        exhibits antibiotic recalcitrance under hypoxic conditions. We also explore the use of a novel therapeutic, chlorate, which kills\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        under O\n                        <jats:sub>2<\/jats:sub>\n                        -limited conditions when the pathogen utilizes anaerobic metabolism (nitrate respiration). Excitingly, we find that chlorate-antibiotic combinations are highly lethal to\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        across a wide range of O\n                        <jats:sub>2<\/jats:sub>\n                        availabilities similar to those the pathogen encounters during infection. Our work demonstrates that we can leverage our understanding of pathogen physiology to propose novel drug combinations that hijack anaerobic metabolism to overcome antibiotic treatment failure in O\n                        <jats:sub>2<\/jats:sub>\n                        -limited environments.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.01425-25","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T13:00:36Z","timestamp":1759150836000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Hijacking anaerobic metabolism to restore antibiotic efficacy in\n                    <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"91","author":[{"given":"Zealon","family":"Gentry-Lear","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0293rh119","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, University of Oregon","place":["Eugene, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Lopez Padilla","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0293rh119","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, University of Oregon","place":["Eugene, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3291-2138","authenticated-orcid":true,"given":"Melanie A.","family":"Spero","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0293rh119","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biology, University of Oregon","place":["Eugene, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13270"},{"key":"e_1_3_3_3_2","first-page":"1","article-title":"Partial pressure of oxygen in the human body: a general review","volume":"9","author":"Ortiz-Prado E","year":"2019","unstructured":"Ortiz-Prado E, Dunn JF, Vasconez J, Castillo D, Viscor G. 2019. 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