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Extracellularly oxidative activation and inactivation of matured prodrug for cryptic self-resistance in naphthyridinomycin biosynthesis

Yue Zhang,Wan-Hong Wen,Jin-Yue Pu,Mancheng Tang,Liwen Zhang,Chao Peng,Yuquan Xu,G. Tang

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance The shielding strategy for self-resistance in antibiotic biosynthesis from bacteria has been known to employ reversible group-transfer reactions that usually do not directly act on the antibiotic pharmacophore. Typically, the phosphorylation-modified, glycosylation-modified, acetylation-modified, and prepeptide-modified prodrug need to be activated by removing the protection group during or following export and, thereby, employing the hydrolysis reaction as the final step. Herein, we discover an unprecedented oxidative activation and overoxidative inactivation of a matured prodrug; significantly, the oxidation reaction directly deals with the drug warhead and occurs outside the host cells. This cryptic self-resistance mechanism sheds light on antibiotic resistance and the complex biology of extracellular environment. Understanding how antibiotic-producing bacteria deal with highly reactive chemicals will ultimately guide therapeutic strategies to combat the increasing clinical resistance crisis. Here, we uncovered a distinctive self-defense strategy featured by a secreted oxidoreductase NapU to perform extracellularly oxidative activation and conditionally overoxidative inactivation of a matured prodrug in naphthyridinomycin (NDM) biosynthesis from Streptomyces lusitanus NRRL 8034. It was suggested that formation of NDM first involves a nonribosomal peptide synthetase assembly line to generate a prodrug. After exclusion and prodrug maturation, we identified a pharmacophore-inactivated intermediate, which required reactivation by NapU via oxidative C-H bond functionalization extracellularly to afford NDM. Beyond that, NapU could further oxidatively inactivate the NDM pharmacophore to avoid self-cytotoxicity if they coexist longer than necessary. This discovery represents an amalgamation of sophisticatedly temporal and spatial shielding mode conferring self-resistance in antibiotic biosynthesis from Gram-positive bacteria.

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