Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics

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.

Influence of cationic groups on the antibacterial behavior of cationic nano-sized hyperbranched polymers to enhance bacteria-infected wound healing

“…The results further indicated that Q 12 -CNHBP was less likely to induce bacteria to develop resistance compared to conventional antibiotics that target specific intracellular materials. 55–58…”

Potent Antibiotic Lemonomycin: A Glimpse of Its Discovery, Origin, and Chemical Synthesis

“…Very recently, Tang and coworkers reported an interesting mechanism of self-resistance when the bacterial host produced lemonomycin and naphthyridinomycin [21]. In the fermentation of S. candidus LL-AP191, 16-dehydroxy-LMM (1a), was identified instead of LMM (Scheme 4).…”

“…The self-resistance strategy poses a challenge to develop a sophisticated biosynthetic pathway to reharvest such potent antibiotics in engineered biosynthetic machinery [22]. Very recently, Tang and coworkers reported an interesting mechanism of self-resistance when the bacterial host produced lemonomycin and naphthyridinomycin [21]. In the fermentation of S. candidus LL-AP191, 16-dehydroxy-LMM (1a), was identified instead of LMM (Scheme 4).…”

“…Fragment 18 could be readily constructed by the aryl boronic ester 20 and vinyl iodide 21 via Suzuki cross-coupling. The characteristic diazobicy- Very recently, Tang and coworkers reported an interesting mechanism of self-resistance when the bacterial host produced lemonomycin and naphthyridinomycin [21]. In the fermentation of S. candidus LL-AP191, 16-dehydroxy-LMM (1a), was identified instead of LMM (Scheme 4).…”

Biosynthesis of DNA-Alkylating Antitumor Natural Products

“…Furthermore, a FAD-binding oxidoreductase NapU encoded in BGC of NDM was reported to activate and inactivate the matured prodrug by extracellular oxidation conferring self-protection [ 113 ]. Recently, a short-chain dehydrogenase NapW mediated the reduction of the hemiaminal pharmacophore, implicating another level of the self-resistance mechanism of the tetrahydroisoquinoline family [ 114 ].…”