Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics

Wan-Hong Wen, Yue Zhang, Ying-Ying Zhang, Qian Yu, Chu-Chu Jiang, Man-Cheng Tang, Jin-Yue Pu, Lian Wu, Yi-Lei Zhao, Ting Shi (), Jiahai Zhou () and Gong-Li Tang ()
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Wan-Hong Wen: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yue Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ying-Ying Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Qian Yu: Shanghai Jiao Tong University
Chu-Chu Jiang: Shanghai Jiao Tong University
Man-Cheng Tang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Jin-Yue Pu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Lian Wu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yi-Lei Zhao: Shanghai Jiao Tong University
Ting Shi: Shanghai Jiao Tong University
Jiahai Zhou: Chinese Academy of Sciences
Gong-Li Tang: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.

Date: 2021
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DOI: 10.1038/s41467-021-27404-3

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