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.
Highlights
Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore
Continuous efforts on elucidation for different kinds of self-resistance mechanisms based on natural product biosynthesis will enrich our knowledge about enzyme-catalyzed inactivation of antibiotics, which may include the other enzyme-reactions acting on the pharmacophore beyond hydrolysis
This raises an open question: how the inactivated intermediate 12 is generated in cytoplasm and which enzyme is responsible for inactivating the hemiaminal pharmacophore (Fig. 1c)? Here, we solved these mysteries by elucidating an intracellularly reductive inactivation of NDM catalyzed by NapW and homW, which belong to shortchain dehydrogenase/reductase (SDR) family encoded by genes napW within biosynthetic gene cluster (BGC) and homW outside BGC, respectively
Summary
Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, and exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics. Tetrahydroisoquinoline (THIQ) antibiotics, with a special THIQ framework, have attracted continuous studies due to the complex polycyclic structures and excellent biological activities against bacteria and tumor cells[11,12,13] This family of natural products includes more than 60 members exemplified by naphthyridinomycin (NDM, 1), saframycin S (SFM-S, 5), ecteinascidin. The substrate promiscuity of SDR proteins thereby provides the detoxification protection in cytoplasm during the biosynthetic pathway and general immunity toward THIQ antibiotics, and expands the known enzymatic reactions for pharmacophore modification beyond hydrolysis
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