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Volume 170, Issue 6

Effects of quorum sensing–interfering agents, including macrolides and furanone C-30, and an efflux pump inhibitor on nitrosative stress sensitivity in Open Access

Graphical Abstract

Graphical Abstract

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Abstract

Long-term administration of certain macrolides is efficacious in patients with persistent pulmonary infection, despite how limited the clinically achievable concentrations are, being far below their MICs. An increase in the sub-MIC of macrolide exposure-dependent sensitivity to nitrosative stress is a typical characteristic of . However, a few clinical isolates do not respond to sub-MIC of macrolide treatment. Therefore, we examined the effects of sub-MIC of erythromycin (EM) on the sensitivity to nitrosative stress together with an efflux pump inhibitor (EPI) phenylalanine arginyl β-naphthylamide (PAβN). The sensitivity to nitrosative stress increased, suggesting that the efflux pump was involved in inhibiting the sub-MIC of macrolide effect. Analysis using efflux pump-mutant revealed that MexAB-OprM, MexXY-OprM, and MexCD-OprJ are factors in reducing the sub-MIC of macrolide effect. Since macrolides interfere with quorum sensing (QS), we demonstrated that the QS–interfering agent furanone C-30 (C-30) producing greater sensitivity to nitric oxide (NO) stress than EM. The effect of C-30 was decreased by overproduction of MexAB-OprM. To investigate whether the increase in the QS–interfering agent exposure-dependent sensitivity to nitrosative stress is characteristic of clinical isolates, we examined the viability of treated with NO. Although treatment with EM could reduce cell viability, a high variability in EM effects was observed. Conversely, C-30 was highly effective at reducing cell viability. Treatment with both C-30 and PAβN was sufficiently effective against the remaining isolates. Therefore, the combination of a QS–interfering agent and an EPI could be effective in treating infections.

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  • Accepted:
  • Published Online:
Keyword(s): efflux pump , efflux pump inhibitor , macrolide , nitrosative stress , P. aeruginosa and quorum sensing–interfering agent
Funding
This study was supported by the:
  • Japan Agency for Medical Research and Development (Award JP18jk021007)
    • Principle Award Recipient: TakeshiShimizu
  • Japan Society for the Promotion of Science (Award 20K07474)
    • Principle Award Recipient: TakeshiShimizu
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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Effects of quorum sensing–interfering agents, including macrolides and furanone C-30, and an efflux pump inhibitor on nitrosative stress sensitivity in Pseudomonas aeruginosa
Microbiology 170, 001464 (2024); https://doi.org/10.1099/mic.0.001464
/content/journal/micro/10.1099/mic.0.001464
/content/journal/micro/10.1099/mic.0.001464
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