Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases.
Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases.
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DOI：
10.1038/s41467-022-34771-y
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发表时间：
2022-12-08
影响因子：
16.6
通讯作者：
Shintani, Yasunori
中科院分区：
文献类型：
--
作者：
Nishida, Yuya;Yanagisawa, Sachiko;Morita, Rikuri;Shigematsu, Hideki;Shinzawa-Itoh, Kyoko;Yuki, Hitomi;Ogasawara, Satoshi;Shimuta, Ken;Iwamoto, Takashi;Nakabayashi, Chisa;Matsumura, Waka;Kato, Hisakazu;Gopalasingam, Chai;Nagao, Takemasa;Qaqorh, Tasneem;Takahashi, Yusuke;Yamazaki, Satoru;Kamiya, Katsumasa;Harada, Ryuhei;Mizuno, Nobuhiro;Takahashi, Hideyuki;Akeda, Yukihiro;Ohnishi, Makoto;Ishii, Yoshikazu;Kumasaka, Takashi;Murata, Takeshi;Muramoto, Kazumasa;Tosha, Takehiko;Shiro, Yoshitsugu;Honma, Teruki;Shigeta, Yasuteru;Kubo, Minoru;Takashima, Seiji;Shintani, Yasunori
抗菌素耐药性是一个全球性的健康问题。尽管在过去十年中做出了巨大努力，但来自某些物种的威胁，包括具有抗药性的淋球菌，仍在继续上升，并将变得无法治愈。开发具有不同作用机制的抗生素是非常必要的。在这里，我们确定了埋藏在真核生物线粒体血红素-铜氧化酶(HCOs)中的变构抑制部位，HCOs是生命所必需的呼吸酶。在细菌和真核生物中，HCOs结合口袋周围的空间构象是高度保守的，但后者有一个额外的螺旋。这种保守变构的结构差异使我们能够合理地确定细菌HCO特异性抑制剂：一种针对头孢曲松耐药淋病奈瑟菌的抗生素化合物。分子动力学结合共振拉曼光谱和停流光谱揭示了底物通道中的变构阻碍是抑制作用的一种机制。我们的方法在调节蛋白质功能方面开辟了新的途径，并拓宽了我们克服AMR的选择。对现有抗生素的抗菌素耐药性需要抗生素的创新。在这里，作者确定了一种产生能量的酶的关键抑制部位，这可以导致抗生素的合理设计。
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. Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.
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影响因子：
4.3
作者：
Borisov, Vitaliy B.;Gennis, Robert B.;Hemp, James;Verkhovsky, Michael I.
通讯作者：
Verkhovsky, Michael I.
影响因子：
4.6
作者：
Gonska N;Young D;Yuki R;Okamoto T;Hisano T;Antonyuk S;Hasnain SS;Muramoto K;Shiro Y;Tosha T;Ädelroth P
通讯作者：
Ädelroth P
影响因子：
64.8
作者：
IWATA, S;OSTERMEIER, C;MICHEL, H
通讯作者：
MICHEL, H
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
树突镜：大型系统发育树的互动观众。
影响因子：
3
作者：
Huson, Daniel H.;Richter, Daniel C.;Rausch, Christian;Dezulian, Tobias;Franz, Markus;Rupp, Regula
通讯作者：
Rupp, Regula