Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases

Yuya Nishida, Sachiko Yanagisawa, Rikuri Morita, Hideki Shigematsu, Kyoko Shinzawa-Itoh, Hitomi Yuki, Satoshi Ogasawara, Ken Shimuta, Takashi Iwamoto, Chisa Nakabayashi, Waka Matsumura, Hisakazu Kato, Chai Gopalasingam, Takemasa Nagao, Tasneem Qaqorh, Yusuke Takahashi, Satoru Yamazaki, Katsumasa Kamiya, Ryuhei Harada, Nobuhiro Mizuno, Hideyuki Takahashi, Yukihiro Akeda, Makoto Ohnishi, Yoshikazu Ishii, Takashi Kumasaka, Takeshi Murata, Kazumasa Muramoto, Takehiko Tosha, Yoshitsugu Shiro, Teruki Honma, Yasuteru Shigeta, Minoru Kubo, Seiji Takashima and Yasunori Shintani ()
Additional contact information
Yuya Nishida: National Cerebral and Cardiovascular Center
Sachiko Yanagisawa: University of Hyogo
Rikuri Morita: University of Tsukuba
Hideki Shigematsu: RIKEN SPring-8 Center
Kyoko Shinzawa-Itoh: University of Hyogo
Hitomi Yuki: RIKEN Center for Biosystems Dynamics Research
Satoshi Ogasawara: Chiba University
Ken Shimuta: National Institute of Infectious Diseases
Takashi Iwamoto: Osaka University Graduate School of Frontier Biological Science
Chisa Nakabayashi: National Cerebral and Cardiovascular Center
Waka Matsumura: University of Hyogo
Hisakazu Kato: Osaka University Graduate School of Frontier Biological Science
Chai Gopalasingam: RIKEN SPring-8 Center
Takemasa Nagao: National Cerebral and Cardiovascular Center
Tasneem Qaqorh: National Cerebral and Cardiovascular Center
Yusuke Takahashi: National Cerebral and Cardiovascular Center
Satoru Yamazaki: National Cerebral and Cardiovascular Center
Katsumasa Kamiya: Kanagawa Institute of Technology
Ryuhei Harada: University of Tsukuba
Nobuhiro Mizuno: Japan Synchrotron Radiation Research Institute
Hideyuki Takahashi: National Institute of Infectious Diseases
Yukihiro Akeda: National Institute of Infectious Diseases
Makoto Ohnishi: National Institute of Infectious Diseases
Yoshikazu Ishii: Toho University School of Medicine
Takashi Kumasaka: Japan Synchrotron Radiation Research Institute
Takeshi Murata: Chiba University
Kazumasa Muramoto: University of Hyogo
Takehiko Tosha: RIKEN SPring-8 Center
Yoshitsugu Shiro: University of Hyogo
Teruki Honma: RIKEN Center for Biosystems Dynamics Research
Yasuteru Shigeta: University of Tsukuba
Minoru Kubo: University of Hyogo
Seiji Takashima: Osaka University Graduate School of Frontier Biological Science
Yasunori Shintani: National Cerebral and Cardiovascular Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Antimicrobial resistance (AMR) is a global health problem. Despite the enormous efforts made in the last decade, threats from some species, including drug-resistant Neisseria gonorrhoeae, continue to rise and would become untreatable. The development of antibiotics with a different mechanism of action is seriously required. Here, we identified an allosteric inhibitory site buried inside eukaryotic mitochondrial heme-copper oxidases (HCOs), the essential respiratory enzymes for life. The steric conformation around the binding pocket of HCOs is highly conserved among bacteria and eukaryotes, yet the latter has an extra helix. This structural difference in the conserved allostery enabled us to rationally identify bacterial HCO-specific inhibitors: an antibiotic compound against ceftriaxone-resistant Neisseria gonorrhoeae. Molecular dynamics combined with resonance Raman spectroscopy and stopped-flow spectroscopy revealed an allosteric obstruction in the substrate accessing channel as a mechanism of inhibition. Our approach opens fresh avenues in modulating protein functions and broadens our options to overcome AMR.

Date: 2022
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DOI: 10.1038/s41467-022-34771-y

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