Effect of sub-minimum inhibitory concentrations of macrolides on sensitivity against nitrosative stress in Pseudomonas aeruginosa
Previous studies have reported that long-term low-dose administration of certain macrolides is efficacious in patients with persistent pulmonary Pseudomonas aeruginosa infections. In the present study, we examined the effect of sub-minimum inhibitory concentrations (sub-MICs) of macrolide antibiotics on growth, biofilm formation and sensitivity against nitrosative stress of P. aeruginosa PAO1. Sub-MICs of the 14-membered macrolides, erythromycin (EM) and clarithromycin (CAM), decreased growth and biofilm formation, and increased sensitivity against nitrosative stress of P. aeruginosa, indicating that administration of sub-MICs of the 14-membered macrolides was effective against P. aeruginosa. However, a 16-membered macrolide, josamycin (JM), was not or less effective. To investigate whether increase in macrolide exposure-dependent sensitivity against nitrosative stress was a typical characteristic of P. aeruginosa, we examined the viabilities of other P. aeruginosa strains treated with an NO donor with or without EM. In non-multidrug-resistant P. aeruginosa (non-MDRP), sub-MIC of EM significantly induced loss of viability following treatment with an NO donor. Furthermore, in high-risk clone ST235 which was a major group in multidrug-resistant P. aeruginosa (MDRP), sub-MIC of EM could effectively induce decreases of the viabilities of MDRP treated with an NO donor. These results suggest that the effect of sub-MIC macrolide treatment on the sensitivity of P. aeruginosa against nitrosative stress form one of explanations for the positive effects of long-term low-dose macrolide therapy.