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TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae

The Journal of Antibiotics volume 75, pages 98–107 (2022)Cite this article

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Abstract

The emergence of multi-drug resistant pathogenic bacteria, especially Gram-negative bacteria, is a worldwide health problem. New antibiotics directed at previously unexplored targets are urgently needed to overcome resistance to existing antibiotic classes. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an attractive target for a new antibacterial agent. Although a number of LpxC inhibitors have been identified, none have been approved as antibacterial agents. These LpxC inhibitors contain a hydroxamate moiety, which is a robust zinc ion chelator. The nonspecific inhibition of metalloenzymes through zinc ion chelation is one of possibilities leading to unwanted side effects. Herein, we report that TP0586532, a non-hydroxamate LpxC inhibitor, has a broad spectrum of antibacterial activity against carbapenem-resistant Enterobacteriaceae. The MIC90 of TP0586532 against clinical isolates of carbapenem-resistant Klebsiella pneumoniae was 4 μg ml−1. TP0586532 also showed an in vivo efficacy against murine systemic, urinary tract and lung infection models caused by meropenem- or ciprofloxacin-resistant strains. The estimated maximum unbound plasma concentration value at the effective dose of TP0586532 in murine infection models was around 13 μg ml−1. TP0586532 is predicted to exhibit a in vivo efficacy without cardiovascular toxicity and showed the potential of non-hydroxamate LpxC inhibitors as antibacterial agents against carbapenem-resistant Enterobacteriaceae.

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Acknowledgements

We thank Dr. Yusuke Honma for helpful discussions and technical support with the experiments, Ms. Ai Shoji, Mr. Tomonori Aida, and Ms. Satoko Murakami for technical support with the experiments, and Mr. Fumihito Ushiyama for the synthesis of TP0586532. The MICs against carbapenem-resistant K. pneumoniae isolated in the United States between 2017 and 2018 were tested by JMI Laboratories. This research did not receive any specific grants from any funding agencies in the public, commercial, or not-for-profit sectors.

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  1. These authors contributed equally: Kiyoko Fujita, Iichiro Takata

Authors and Affiliations

  1. Taisho Pharmaceutical Co., Ltd, Saitama, Japan

    Kiyoko Fujita, Iichiro Takata, Ippei Yoshida, Hirotoshi Okumura, Katsumasa Otake, Hajime Takashima & Hiroyuki Sugiyama

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  1. Kiyoko Fujita
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Contributions

KF, IT, IY, HO, and KO conducted the experiments and analyzed the data. HS and HT developed the concept and secured the project management and resources. KF, IT, HO, and HS wrote and revised the manuscript. All authors approved the final manuscript.

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Correspondence to Hiroyuki Sugiyama.

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Fujita, K., Takata, I., Yoshida, I. et al. TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae. J Antibiot 75, 98–107 (2022). https://doi.org/10.1038/s41429-021-00486-3

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