Potentiation of Aminoglycoside Activity in Pseudomonas aeruginosa by Targeting the AmgRS Envelope Stress-Responsive Two-Component System

• DOI: 10.1128/aac.03069-15
• Publication Date: 2016-03-29T02:23:38Z
• Authors: Keith Poole; Christie Gilmour; Maya A. Farha; Erin Mullen; Calvin Ho-Fung Lau; Eric D. Brown
• Keywords: 0301 basic medicine; Ribostamycin; Paromomycin; Membrane Proteins; Drug Synergism; Gene Expression Regulation, Bacterial; Microbial Sensitivity Tests; Anti-Bacterial Agents; 3. Good health; 03 medical and health sciences; Bacterial Proteins; Stress, Physiological; Drug Resistance, Multiple, Bacterial; Pseudomonas aeruginosa; Humans; Pseudomonas Infections; Gentamicins; Rifampin; Amikacin; Heat-Shock Proteins

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.