4.5 Article

SolS-catalyzed sulfoxidation of labionin to solabionin drives antibacterial activity of solabiomycins

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2023.129323

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RiPP; Lipolanthine; Sulfoxide; Monooxygenase; Antibiotic

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We discovered solabiomycins, a new class of lipopeptides with polar-functionalized fatty acyl groups, through genome mining and stable isotope labeling. These solabiomycins contain a sulfoxide group in the labionin moiety called solabionin. Our study demonstrated that the sulfoxide is critical for the antibacterial activity of solabiomycins against Gram-positive bacteria. We also characterized the catalytic activity of SolS, which is involved in the sulfoxidation of solabionin, and determined its role in converting deoxysolabiomycins to solabiomycins.
Ribosomally synthesized and posttranslationally modified peptides (RiPPs) with polar-functionalized fatty acyl groups are newly found lipopeptide-class natural products. We recently employed a combined approach of genome mining and stable isotope labeling and discovered solabiomycins as one of the polar-functionalized fatty-acylated RiPPs (PFARs) from Streptomyces lydicus NBRC13058. The solabiomycins contained a characteristic sulfoxide group in the labionin moiety referred to as the 'solabionin' structure for the RiPP moiety. A previous gene knockout experiment indicated that solS, which encodes a putative flavin adenine dinucleotide (FAD)-nicotinamide adenine dinucleotide (phosphate) (NAD(P))-binding protein, is involved in the sulfoxidation of an alkyl sulfide in the solabionin. In this study, we isolated deoxysolabiomycins A and B from Delta solS mutant and fully determined the chemical structures using a series of NMR experiments. We also tested the bioactivity of deox-ysolabiomycins against Gram-positive bacteria, including Mycolicibacterium smegmatis, and notably found that the sulfoxide is critical for the antibacterial activity. To characterize the catalytic activity of SolS, the recom-binant protein was incubated with a putative substrate, deoxysolabiomycins, and the cofactors FAD and NADPH. In vitro reactions demonstrated that SolS catalyzes the sulfoxidation, converting deoxysolabiomycins to solabiomycins.

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