CytA, a reductase in the cytorhodin biosynthesis pathway, inactivates anthracycline drugs in Streptomyces

Abstract

Antibiotic-producing microorganism can develop strategies to deal with self-toxicity. Cytorhodins X and Y, cosmomycins A and B, and iremycin, are produced as final products from a marine-derived Streptomyces sp. SCSIO 1666. These C-7 reduced metabolites show reduced antimicrobial and comparable cytotoxic activities relative to their C-7 glycosylated counterparts. However, the biosynthetic mechanisms and relevant enzymes that drive C-7 reduction in cytorhodin biosynthesis have not yet been characterized. Here we report the discovery and characterization of a reductase, CytA, that mediates C-7 reduction of this anthracycline scaffold; CytA endows the producer Streptomyces sp. SCSIO 1666 with a means of protecting itself from the effects of its anthracycline products. Additionally, we identified cosmomycins C and D as two intermediates involved in cytorhodin biosynthesis and we also broadened the substrate specificity of CytA to clinically used anthracycline drugs.

Diversity, function and assembly of mangrove root-associated microbial communities at a continuous fine-scale

“…Carbon cycling requires a variety of carbohydrate-active enzymes 33 , including GTs 34 . Some GTs in wheat root environments could help resist pathogenic fungi 35 , whereas other GTs had a self-detoxification mechanism 36 . Also, some GTs could catalyze the activation of hormones in plants and improve the transport efficiency of sugars in roots 34 .…”

Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics

“…However, these modifications are usually limited by reversible group-transfer reactions acting on end-products, such as methylation, acylation, phosphorylation, glycosylation, amino-, or peptide-acylation and so on 1 , 36 . Rare cases employing reductive reaction include virginiamycin M1 reductase-catalyzed conversion of a ketone to alcohol 37 , a nitroreductase-mediated chloramphenicol inactivation and CytA-catalyzed dehydroxylation of cytorhodin 38 , 39 , as well as two recently-discovered fungal examples including a multistep reduction cascade in monasone naphthoquinone and a redox-cycle in A26771B biosynthesis 33 , 40 . Most of these modifications change the structure of antibiotics to prevent them from binding to the responding cellular target inside the cell rather than destroy the pharmacophore.…”

Enhancement of edeine production in Brevibacillus brevis X23 via in situ promoter engineering

“…Bacillus subtilis 168 was used to evaluate the antimicrobial activity of B . brevis X23 and the six promoter‐engineered B. brevis strains through Kirby‐Bauer disk diffusion according to a previous study (Gui et al ., 2019 ). The B .…”

“…Each filtrate (10 μl) was added to the center of the paper disk. Sterile LB liquid media served as a negative control (Gui et al ., 2019 ). The plates were incubated for 24 h at 30°C, and the inhibition zone was measured.…”

“…Genetic engineering, such as promoter modification, deletion or overexpression of regulatory factors, feeding with key precursors and increasing BGC copy number, has significantly improved the production of antibiotics (Marahiel et al, 1987;Keeney et al, 2008;Zhang et al, 2016;Zhang et al, 2019). Promoter engineering (native promoter replacement with stronger ones) is one of the most effective ways to improve antibiotic production.…”