Regio-selectively reduced streptogramin A analogue, 5,6-dihydrovirginiamycin M₁ exhibits improved potency against MRSA

Abstract

Significance and Impact of the Study: This study demonstrates the expanded applicability of the unique bio-hydrogenation activity of Streptomyces venezuelae towards macrocyclic lactone streptogramin A antibiotic and evaluates the enhanced anti-MRSA activity of the bioconverted analogue. The unique bio-catalytic feature of S. venezuelae could contribute to the biosynthesis and reconstruction of diverse therapeutic resources, particularly as a promising scaffold tailoring tool for creating antimicrobial agents with possibly improved therapeutic effects. AbstractA newly reduced macrocyclic lactone antibiotic streptogramin A, 5,6-dihydrovirginiamycin M 1 was created by feeding virginiamycin M 1 into a culture of recombinant Streptomyces venezuelae. Its chemical structure was spectroscopically elucidated, and this streptogramin A analogue showed twofold higher antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) compared with its parent molecule virginiamycin M 1 . Docking studies using the model of streptogramin A acetyltransferase (VatA) suggested that the newly generated analogue binds tighter with overall lower free energy compared with the parent molecule virginiamycin M1. This hypothesis was validated experimentally through the improvement of efficacy of the new analogue against MRSA strains. The biotransformation approach presented herein could have a broad application in the production of reduced macrocyclic molecules.

Engineering actinomycetes for biosynthesis of macrolactone polyketides

“…This changes in natural scaffold oligomycin and tilmicosin brought increased activity against S. cerevisiae and Bacillus subtilis respectively [133]. Similarly, macrocyclic lactone antibiotic streptogramin A namely 5, 6-dihydrovirginiamycin M1 was created by feeding virginiamycin M1 into a culture of recombinant S. venezuelae through the mechanism of bio-dehydrogenation catalysis [134]. The generated analog showed enhanced anti-MRSA activity compared to the parent compound.…”

Potential for Reduction of Streptogramin A Resistance Revealed by Structural Analysis of Acetyltransferase VatA

“…Consistent with this notion, the same region in this antibiotic molecule was previously identified as an avenue for the development of acetylation-resilient derivatives (9). As further validation of the importance of VatA Pro108 and Leu113 in the binding affinity for streptogramin A substrates, a recent study demonstrated that a derivative of virginiamycin M1 with a modification in this region (saturation of the C-28 -C-29 bond) that is expected to interact with these two residues showed altered binding affinity to VatA (25).…”