Roseocin, a novel two-peptide lantibiotic from Streptomyces roseosporus discovered in our lab, carries extensive lanthionine (Lan) and methyllanthionine (MeLan) thioether cross-links in both peptides. The two peptides, containing 33 and 35 residues, display synergistic antibacterial activity against Gram-positive pathogens. We used a systematic approach to assign the ring pattern of the alpha component of roseocin, whereby six individual ring variants were created. Four Ser/Thr residues that are dehydrated during biosynthesis and two Cys involved in cyclization were substituted individually with Ala. The data with these variants suggest that Cys10 partners with Ser2 to form Lan ring A, Cys11 partners with Thr7 to form MeLan ring B, Ser18 partners with Cys23 to generate Lan ring C, and Thr21 partners with Cys27 to form MeLan ring D. The stereochemistry of all lanthionine and methyllanthionine residues was shown to be DL by Marfey's analysis. Disruption of Lan rings of Rosα impacted both the structure and bioactivity while the MeLan rings were expendable but important for roseocin's bioactivity as their disruption led to a substantial increase in MIC. The installation of its two Lan rings is proposed to be decisive to attain the native ring pattern, essential for its synergistic antibacterial activity with Rosβ.
Kishen et al. (Mon,) studied this question.