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An efflux pump deletion mutant enabling the discovery of a macrolide as an overlooked anti-P. aeruginosa active compound

The Journal of Antibiotics volume 76, pages 301–303 (2023)Cite this article

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Abstract

Antimicrobial resistance is a serious, worldwide problem. Pseudomonas aeruginosa (P. aeruginosa) is the pathogen that poses a major threat to human health. However, resistance-nodulation-cell division type multidrug efflux pump systems defend P. aeruginosa from many antibiotics. Therefore, only limited therapeutic drugs are available. In this regard, we screened overlooked anti- P. aeruginosa compounds from the Ōmura Natural Compound library using an efflux pump deletion P. aeruginosa mutant strain, YM64, which led us to find a semisynthetic macrolide, 5-O-mycaminosyltylonolide, whose anti- P. aeruginosa activity against a standard laboratory adapted strain, PAO1, was enhanced by an efflux pump inhibitor, phenylalanine-arginine beta-naphthylamide.

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References

  1. Murray CJL, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399:629–55.

    Article  CAS  Google Scholar 

  2. Willyard C. The drug-resistant bacteria that pose the greatest health threats. Nature. 2017;543:15.

    Article  CAS  PubMed  Google Scholar 

  3. Bodey GP, Bolivar R, Fainstein V, Jadeja L. Infections caused by Psudomonas aeruginosa. Rev Infect Dis. 1983;5:279–313.

    Article  CAS  PubMed  Google Scholar 

  4. Malhotra S, Hayes D Jr, Wozniak DJ. Cystic fibrosis and Pseudomonas aeruginosa: the host-microbe interface. Clin Microbiol Rev. 2019;32:e00138–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stoitsova SO, Bruan Y, Ullrich MS, Weingart H. Charactarization of the RND-type multidrug efflux pump MexAB-OprM of the plant pathogen Pseudomonas syringae. Appl Environ Microbiol. 2008;74:3387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ferrer-Espada R, Shahrour H, Pitts B, Stewart PS, Sánchez-Gómez S, Martínez-De-Tejada G. A permeability-increasing drug synergizes with bacterial efflux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains. Sci Rep. 2019;9:3452.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Morita Y, Komori Y, Mima T, Kuroda T, Mizushima T, Tsuchiya T. Construction of a series of mutants lacking all of the four major mex operons for multidrug efflux pumps or possessing each one of the operons from Pseudomonas aeruginosa PAO1: MexCD-OprJ is an inducible pump. FEMS Microbiol Lett. 2001;202:139–43.

    Article  CAS  PubMed  Google Scholar 

  8. Mima T, Kohira N, Li Y, Sekiya H, Ogawa W, Kuroda T, et al. Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND coomponents in Pseudomonas aeruginosa. Microbiolgy. 2009;155:3509–17.

    Article  CAS  Google Scholar 

  9. Ōmura S. Microbial metabolites: 45years of wandering, wondering and discovering. Tetrahedron. 2011;67:6420–59.

    Article  Google Scholar 

  10. Ishiyama A, Hokari R, Nonaka K, Chiba T, Miura H, Otoguro K, et al. Diatretol, an å, a’-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial. J Antibiot. 2021;74:266–68.

    Article  CAS  Google Scholar 

  11. Kobayashi C, Watanabe Y, Oshima M, Hirose T, Yamasaki M, Iwamoto M, et al. Fungal secondary metabolite exophillic acid selectively inhibits the entry of hepatitis B and D viruses. Viruses. 2022;14:764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kondo N, Kimishima A, Maruyama S, Sato M, Yuge H, Ohta Y, et al. The establishment of a high-sensitive insecticidal activity detection system using silkworm first instar larvae enables efficiently search for insecticide seed compounds. ACS Agric Sci Technol. 2023. https://doi.org/10.1021/acsagscitech.2c00293.

  13. Phan LT, Qui YL, Or YS, Vo NH, Jian T, Hou Y, Busuyek M. 23-O-Substituted 5-O-Mycaminosyltylonide Derivatives. WO03089446A2 (2003).

  14. Lamers RP, Cavallari JF, Burrows LL. The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAβN) permeabilizes the outer membrane of gram-negative bacteria. PLoS One. 2013;8:e60666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial ausceptibility testing, 32nd Edition. (2022). Available from: https://clsi.org.

  16. Leber AL, et al. Clinical microbiology procedures handbook. Volume 1–3, 4th ed. ASM Press; 2016. American Society for Microbiology.

  17. Sugawara A, Maruyama H, Shibusawa S, Matsui H, Hirose T, Tsutsui A, et al. 5-O-Mycaminosyltylonolide antibacterial derivatives: design, synthesis and bioactivity. J Antibiot. 2017;70:878–87.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Distinguished Emeritus Professor Satoshi Ōmura (Kitasato University) for his helpful support and valuable suggestions. We thank to Koichi Shiraishi, and Souhei Tanabe (Kowa Company) for valuable advice. This study was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS), the Japan Agency for Medical Research & Development (AMED) under Grant Number JP21am0101096 and JP22ama121035.

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Author notes

  1. These authors contributed equally: Aoi Kimishima, Kazunari Sakai, Masako Honsho

Authors and Affiliations

  1. Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Aoi Kimishima, Masako Honsho, Hidehito Matsui, Yoshihiro Watanabe, Masato Iwatsuki, Toshiaki Sunazuka, Hideaki Hanaki & Yukihiro Asami

  2. Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, 108-8641, Japan

    Aoi Kimishima, Masako Honsho, Hidehito Matsui, Yoshihiro Watanabe, Masato Iwatsuki, Toshiaki Sunazuka, Hideaki Hanaki & Yukihiro Asami

  3. Research Management Department, Kowa Company LTD., 4-13-3 Nihonbashi-honcho, Chuo-ku, Tokyo, 103-8433, Japan

    Kazunari Sakai, Naoaki Arima, Kazutoyo Abe & Hideaki Hanaki

  4. University of Florida College of Medicine, Gainesville, FL, USA

    Paul Wasuwanich

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  1. Aoi Kimishima
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Correspondence to Yukihiro Asami.

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Kimishima, A., Sakai, K., Honsho, M. et al. An efflux pump deletion mutant enabling the discovery of a macrolide as an overlooked anti-P. aeruginosa active compound. J Antibiot 76, 301–303 (2023). https://doi.org/10.1038/s41429-023-00607-0

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  • DOI: https://doi.org/10.1038/s41429-023-00607-0

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