MODE OF ACTION OF THE LANTIBIOTIC MERSACIDIN - INHIBITION OF PEPTIDOGLYCAN BIOSYNTHESIS VIA A NOVEL MECHANISM

Mersacidin is an antibiotic peptide produced by Bacillus sp. strain HI L Y-85,54728 that belongs to the group of lantibiotics. Its activity i n vivo against methicillin-resistant Staphylococcus aureus strains com pares with that of the glycopeptide antibiotic vancomycin (S. Chatterj ee, D. K. Chatterjee, R. H. Jani, J. Blumbach, B. N. Ganguli, N. Klese l, M. Limbert, and G. Seibert, J. Antibiot, 45:839-845, 1992). Incubat ion of Staphylococcus simulans 22 with mersacidin resulted in the cess ation of growth and slow lysis. Biosyntheses of DNA, RNA, and protein were not affected, whereas incorporation of glucose and D-alanine was inhibited and a regular reduction in the level of cell wall thickness was observed. Thus, unlike type A lantibiotics, mersacidin does not fo rm pores in the cytoplasmic membrane but rather inhibits cell wall bio synthesis. Comparison with tunicamycin-treated cells indicated that pe ptidoglycan rather than teichoic acid metabolism is primarily affected . Mersacidin caused the excretion of a putative cell wall precursor in to the culture supernatant. The formation of polymeric peptidoglycan w as effectively inhibited in an in vitro assay, probably on the level o f transglycosylation. In contrast to vancomycin, the activity of mersa cidin was not antagonized by the tripeptide diacetyl-L-lys-D-Ala-D-Ala , indicating that on the molecular level its mode of action differs fr om those of glycopeptide antibiotics. These data together with electro n microscopy suggest that mersacidin acts on a novel target, which ope ns new perspectives for the treatment of methicillin-resistant S. aure us.