Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

Abstract

Actinomycetes are prolific producers of natural products, particularly antibiotics. However, a significant proportion of its biosynthetic gene clusters (BGCs) remain silent under typical laboratory conditions. This limits the effectiveness of conventional isolation methods for the discovery of novel natural products. Genetic interventions targeting the activation of silent gene clusters are necessary to address this challenge. Streptomyces antibiotic regulatory proteins (SARPs) act as cluster-specific activators and can be used to target silent BGCs for the discovery of new antibiotics. In this study, the expression of a previously uncharacterized SARP protein, Syo_1.56, in Streptomyces sp. RK18-A0406 significantly enhanced the production of known antimycins and led to the discovery of 12 elasnins (1–12), 10 of which were novel. The absolute stereochemistry of elasnin A₁ was assigned for the first time to be 6S. Unexpectedly, Syo_1.56 seems to function as a pleiotropic rather than cluster-specific SARP regulator, with the capability of co-regulating two distinct biosynthetic pathways, simultaneously. All isolated elasnins were active against wild-type and methicillin-resistant Staphylococcus aureus with IC₅₀ values of 0.5–20 μg/mL, some of which (elasnins A₁, B₂, and C₁ and proelasnins A₁, and C₁) demonstrated moderate to strong antimalarial activities against Plasmodium falciparum 3D7. Elasnins A₁, B₃, and C₁ also showed in vitro inhibition of the metallo-β-lactamase responsible for the development of highly antibiotic-resistant bacterial strains.