{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:30:31Z","timestamp":1787016631967,"version":"build-2736575974"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T00:00:00Z","timestamp":1532649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects on the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, the hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here the testing of paired combinations of four\n                    <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n                    VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), and phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistin-colistimethate sodium (CMS) and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, individual toxins, and their combinations were evaluated by the simultaneous measurement of mitochondrial metabolic, total transcriptional\/translational, and Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100 to 150 \u03bcM) and prompted a significant increase in oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested cell proliferation at clinically achievable (&lt;1 mM) concentrations as well, with CMS displaying surprisingly high cytotoxicity (50% effective dose [ED\n                    <jats:sub>50<\/jats:sub>\n                    ] = 180 \u03bcM) in BEAS-2B cells. The dose-response curves were probed by a median-effect analysis, which established a synergistically enhanced cytotoxicity of the PYO-CMS combination in all three airway cell lines; a particularly strong effect on BEAS-2B cells was observed, with a combination index (CI) of 0.27 at the ED\n                    <jats:sub>50<\/jats:sub>\n                    . PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS-PYO doses. These findings suggest that further evaluations of CMS safety are needed, along with a search for means to moderate potentially cytotoxic interactions.\n                  <\/jats:p>","DOI":"10.1128\/aac.02349-17","type":"journal-article","created":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T05:45:41Z","timestamp":1526449541000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells"],"prefix":"10.1128","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3000-5673","authenticated-orcid":false,"given":"Valeri V.","family":"Mossine","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, Missouri, USA"},{"name":"Experiment Station Chemical Laboratories, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Chance","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri, USA"},{"name":"Department of Child Health, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K.","family":"Waters","sequence":"additional","affiliation":[{"name":"Experiment Station Chemical Laboratories, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Mawhinney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, Missouri, USA"},{"name":"Experiment Station Chemical Laboratories, University of Missouri, Columbia, Missouri, USA"},{"name":"Department of Child Health, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2007.07.004"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/cc3995"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/09298673113209990185"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70850-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(06)70580-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40560-015-0072-9"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.2147\/CE.S64980"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02690-16"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2010.08.001"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2017.05.016"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc071717"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.02.00248102"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2012-202059"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03510-14"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.56.9.2515-2517.1988"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0088OC"},{"key":"e_1_3_3_18_2","first-page":"L61","article-title":"Effects of P. aeruginosa-derived bacterial products on tracheal ciliary function: role of O2 radicals","volume":"260","author":"Jackowski JT","year":"1991","unstructured":"Jackowski JT, Szepfalusi Z, Wanner DA, Seybold Z, Sielczak MW, Lauredo IT, Adams T, Abraham WM, Wanner A. 1991. 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