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

Automated summary

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.