Nitrate Respiration Promotes Polymyxin B Resistance in Pseudomonas aeruginosa

Polymyxin B (PMB) is known to require reactive oxygen species (ROS) for its bactericidal activity, but the mechanism of PMB resistance in various strains has been poorly understood. This study examined the role of nitrate respiration (NR) of some strains in the PMB resistance. We observed that the minimum inhibitory concentration (MIC) value of PMB against PA14 was eightfold reduced (from 2.0 to 0.25 μg/mL) by agitation, but not against PAO1 (from 2.0 to 1.0 μg/mL). Transcriptomic and phenotypic analyses using both strains and their NR mutants revealed that the higher NR in PAO1 than in PA14 accounted for the higher MIC value ( , PMB resistance) of PAO1, which was sufficient to compromise the antibacterial activity of PMB in infections. We also confirmed the contribution of the NR to the PMB resistance is independent of the major catalase (KatA), suggesting that the NR might affect the ROS generation rather than the ROS disintegration. Furthermore, this PMB resistance was relatively common among clinical isolates and correlated with higher NR in those strains. These results suggest strains could display intrinsic resistance to antibiotics in clinical settings and that NR is a crucial factor in the intrinsic antibiotic resistance, and also provide an insight into another key target for successful antibiotic treatment of infections. 34, 442-451.