{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T17:24:37Z","timestamp":1790529877544,"version":"4.1.0"},"reference-count":88,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000082","name":"Cystic Fibrosis Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000082","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            A screen for agents that potentiated the activity of paromomycin (PAR), a 4,5-linked aminoglycoside (AG), against wild-type\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Pseudomonas aeruginosa<\/jats:named-content>\n            identified the RNA polymerase inhibitor rifampin (RIF). RIF potentiated additional 4,5-linked AGs, such as neomycin and ribostamycin, but not the clinically important 4,6-linked AGs amikacin and gentamicin. Potentiation was absent in a mutant lacking the AmgRS envelope stress response two-component system (TCS), which protects the organism from AG-generated membrane-damaging aberrant polypeptides and, thus, promotes AG resistance, an indication that RIF was acting via this TCS in potentiating 4,5-linked AG activity. Potentiation was also absent in a RIF-resistant RNA polymerase mutant, consistent with its potentiation of AG activity being dependent on RNA polymerase perturbation. PAR-inducible expression of the AmgRS-dependent genes\n            <jats:italic>htpX<\/jats:italic>\n            and\n            <jats:italic>yccA<\/jats:italic>\n            was reduced by RIF, suggesting that AG activation of this TCS was compromised by this agent. Still, RIF did not compromise the membrane-protective activity of AmgRS, an indication that it impacted some other function of this TCS. RIF potentiated the activities of 4,5-linked AGs against several AG-resistant clinical isolates, in two cases also potentiating the activity of the 4,6-linked AGs. These cases were, in one instance, explained by an observed AmgRS-dependent expression of the MexXY multidrug efflux system, which accommodates a range of AGs, with RIF targeting of AmgRS undermining\n            <jats:italic>mexXY<\/jats:italic>\n            expression and its promotion of resistance to 4,5- and 4,6-linked AGs. Given this link between AmgRS, MexXY expression, and pan-AG resistance in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            , RIF might be a useful adjuvant in the AG treatment of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            infections.\n          <\/jats:p>","DOI":"10.1128\/aac.03069-15","type":"journal-article","created":{"date-parts":[[2016,3,29]],"date-time":"2016-03-29T02:23:38Z","timestamp":1459218218000},"page":"3509-3518","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Potentiation of Aminoglycoside Activity in Pseudomonas aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System"],"prefix":"10.1128","volume":"60","author":[{"given":"Keith","family":"Poole","sequence":"first","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christie","family":"Gilmour","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya A.","family":"Farha","sequence":"additional","affiliation":[{"name":"M. 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