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TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo

The Journal of Antibiotics volume 75, pages 136–145 (2022)Cite this article

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Abstract

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an essential enzyme in the biosynthesis of Lipid A, an active component of lipopolysaccharide (LPS), from UDP-3-O-acyl-N-acetylglicosamine. LPS is a major component of the cell surface of Gram-negative bacteria. LPS is known to be one of causative factors of sepsis and has been associated with high mortality in septic shock. TP0586532 is a novel non-hydroxamate LpxC enzyme inhibitor. In this study, we examined the inhibitory effect of TP0586532 on the LPS release from Klebsiella pneumoniae both in vitro and in vivo. Our results confirmed the inhibitory effect of TP0586532 on LPS release from the pathogenic bacterial species. On the other hand, meropenem and ciprofloxacin increase the level of LPS release. Furthermore, the effects of TP0586532 on LPS release and interleukin (IL)-6 production in the lung were determined using a murine model of pneumonia caused by K. pneumoniae. As observed in the in vitro study, TP0586532 showed the marked inhibitory effect on LPS release in the lungs, whereas meropenem- and ciprofloxacin-treated mice showed higher levels of LPS release and IL-6 production in the lungs as compared to those in the lungs of vehicle-treated mice. Moreover, TP0586532 used in combination with meropenem and ciprofloxacin attenuated the LPS release and IL-6 production induced by meropenem and ciprofloxacin in the lung. These results indicate that the inhibitory effect of TP0586532 on LPS release from pathogenic bacteria might be of benefit in patients with sepsis.

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Acknowledgements

We thank Dr. Yusuke Honma for his helpful discussions and technical support for the experiments, Ms. Ai Shoji, Mr. Tomonori Aida and Ms. Satoko Murakami for their technical support for the experiments, and Mr. Fumihito Ushiyama for the synthesis of TP0586532.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

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

    Kiyoko Fujita, Iichiro Takata, Ippei Yoshida & Hiroyuki Sugiyama

  2. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan

    Hajime Takashima

  3. Medical information, Taisho Pharmaceutical Co., Ltd, Tokyo, Japan

    Hiroyuki Sugiyama

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  1. Kiyoko Fujita
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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, reduces LPS release and IL-6 production both in vitro and in vivo. J Antibiot 75, 136–145 (2022). https://doi.org/10.1038/s41429-021-00498-z

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