{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:02:30Z","timestamp":1785459750377,"version":"3.56.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p><jats:italic>Pseudomonas aeruginosa<\/jats:italic>, a well<jats:bold>-<\/jats:bold>known cause of nosocomial infection, is frequently antibiotic resistant and this complicates treatment. Links between oxidative stress responses inducing antibiotic resistance through over<jats:bold>-<\/jats:bold>production of RND<jats:bold>-<\/jats:bold>type efflux pumps have been reported in <jats:italic>P. aeruginosa<\/jats:italic>, but this has not previously been associated with MFS<jats:bold>-<\/jats:bold>type efflux pumps. Two MFS efflux pumps encoded by <jats:italic>mfs1<\/jats:italic> and <jats:italic>mfs2<\/jats:italic> were selected for study because they were found to be sodium hypochlorite (NaOCl) inducible. Antibiotic susceptibility testing was used to define the importance of these MFS pumps in antibiotic resistance and proteomics was used to characterize the resistance mechanisms involved. The results revealed that <jats:italic>mfs1<\/jats:italic> is NaOCl inducible whereas <jats:italic>mfs2<\/jats:italic> is NaOCl, N<jats:bold>-<\/jats:bold>Ethylmaleimide and t<jats:bold>-<\/jats:bold>butyl hydroperoxide inducible. Deletion of <jats:italic>mfs1<\/jats:italic> or <jats:italic>mfs2<\/jats:italic> did not affect antibiotic or paraquat susceptibility. However, over<jats:bold>-<\/jats:bold>production of Mfs1 and Mfs2 reduced susceptibility to aminoglycosides, quinolones, and paraquat. Proteomics, gene expression analysis and targeted mutagenesis showed that over<jats:bold>-<\/jats:bold>production of the MexXY RND<jats:bold>-<\/jats:bold>type efflux pump in a manner dependent upon <jats:italic>armZ<\/jats:italic>, but not <jats:italic>amgRS<\/jats:italic>, is the cause of reduced antibiotic susceptibility upon over<jats:bold>-<\/jats:bold>production of Mfs1 and Mfs2. <jats:italic>mexXY operon<\/jats:italic> expression analysis in strains carrying various lengths of <jats:italic>mfs1<\/jats:italic> and <jats:italic>mfs2<\/jats:italic> revealed that at least three transmembrane domains are necessary for <jats:italic>mexXY<\/jats:italic> over<jats:bold>-<\/jats:bold>expression and decreased antibiotic susceptibility. Over-expression of the MFS-type efflux pump gene <jats:italic>tetA<\/jats:italic>(C) did not give the same effect. Changes in paraquat susceptibility were independent of <jats:italic>mexXY<\/jats:italic> and <jats:italic>armZ<\/jats:italic> suggesting that it is a substrate of Mfs1 and Mfs2. Altogether, this is the first evidence of cascade effects where the over<jats:bold>-<\/jats:bold>production of an MFS pump causes over<jats:bold>-<\/jats:bold>production of an RND pump, in this case MexXY via increased <jats:italic>armZ<\/jats:italic> expression.<\/jats:p>","DOI":"10.3389\/fmicb.2020.592153","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T07:15:16Z","timestamp":1610522116000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Over-Expression of Hypochlorite Inducible Major Facilitator Superfamily (MFS) Pumps Reduces Antimicrobial Drug Susceptibility by Increasing the Production of MexXY Mediated by ArmZ in Pseudomonas aeruginosa"],"prefix":"10.3389","volume":"11","author":[{"given":"Punyawee","family":"Dulyayangkul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naphat","family":"Satapoomin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"Avison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisanart","family":"Charoenlap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paiboon","family":"Vattanaviboon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skorn","family":"Mongkolsuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.2144\/99265bm05","article-title":"The pKNOCK series of broad-host-range mobilizable suicide vectors for gene knockout and targeted DNA insertion into the chromosome of Gram-negative bacteria.","volume":"26","author":"Alexeyev","year":"1999","journal-title":"Biotechniques"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1128\/JB.184.2.572-576.2002","article-title":"VmrA, a member of a novel class of Na+-coupled multidrug efflux pumps from Vibrio parahaemolyticus.","volume":"184","author":"Chen","year":"2002","journal-title":"J. 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