title: Potentiation of Aminoglycoside Activity in Pseudomonas aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System.
abstract: A screen for agents that potentiated the activity of paromomycin (PAR), a 4,5-linked aminoglycoside (AG), against wild-type Pseudomonas aeruginosa 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 htpX and yccA 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 mexXY 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 P. aeruginosa, RIF might be a useful adjuvant in the AG treatment of P. aeruginosa infections.
authors.affiliation: Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada poolek@queensu.ca.
authors.forename: Keith
authors.initials: K
authors.lastname: Poole
authors.affiliation: Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada.
authors.forename: Christie
authors.initials: C
authors.lastname: Gilmour
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Maya A
authors.initials: MA
authors.lastname: Farha
authors.affiliation: Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Mullen
authors.affiliation: Department of Biomedical and Molecular Sciences, Botterell Hall, Queen's University, Kingston, Ontario, Canada.
authors.forename: Calvin Ho-Fung
authors.initials: CH
authors.lastname: Lau
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004357:Drug Synergism; D015964:Gene Expression Regulation, Bacterial; D005839:Gentamicins / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008826:Microbial Sensitivity Tests; D010303:Paromomycin / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D012271:Ribostamycin / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005839:Gentamicins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; C402791:MexXY protein, Pseudomonas aeruginosa; D012271:Ribostamycin; D010303:Paromomycin; D000583:Amikacin; D012293:Rifampin