PurA is the main target of aurodox, a type III secretion system inhibitor

Author:

Watanabe Yoshihiro12ORCID,Haneda Takeshi3,Kimishima Aoi12,Kuwae Asaomi12,Suga Takuya12,Suzuki Takahiro4,Iwabuchi Yoshiharu4,Honsho Masako12,Honma Sota12,Iwatsuki Masato12,Matsui Hidehito12,Hanaki Hideaki12,Kanoh Naoki45,Abe Akio12,Asami Yukihiro12,Ōmura Satoshi1

Affiliation:

1. Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo 108-8641, Japan

2. Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Tokyo 108-8641, Japan

3. Laboratory of Microbiology, School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan

4. Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan

5. School of Pharmacy and Pharmaceutical Sciences, and Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Society for the Promotion of Science

Publisher

Proceedings of the National Academy of Sciences

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