Mersacidin is an antibiotic peptide produced byThe term lantibiotics designates a group of lanthionine (and/or 3-methyllanthionine)-containing peptides with antibiotic activity against gram-positive bacteria (25). In contrast to peptide antibiotics like bacitracin or gramicidin S (10), lantibiotics are ribosomally synthesized and show unique structural properties, which arise from posttranslational modifications (for reviews, see references 3 and 9).With a molecular mass of 1,825 Da, mersacidin is the smallest lantibiotic known so far. Its propeptide template consists of 20 amino acids, 8 of which are modified to yield 4 thioether amino acids: 3 3-methyllanthionines and 1 2-aminovinyl-2-methylcysteine. This leads to the formation of four intramolecular heterocyclic rings. Additionally, the unusual amino acid ␣,-didehydroalanine is found. Mersacidin carries no net charge and has overall hydrophobic properties (5). It is produced by Bacillus sp. strain HIL Y-85,54728 and is active against several gram-positive bacteria such as streptococci, bacilli, and staphylococci including methicillin-resistant Staphylococcus aureus strains; enterococci are relatively insusceptible (4, 14). Although in vitro mersacidin is less active than vancomycin, teicoplanin, and daptomycin (17), its activity in vivo is at least comparable to that of vancomycin in the treatment of experimental staphylococcal infections (including those caused by methicillin-resistant S. aureus strains) in mice (4,14).In addition to its potential therapeutical value, mersacidin has been the subject of increased interest because of its position among the lantibiotics described so far, which have been classified into two groups (9). The type A lantibiotics (e.g., Pep5 and nisin) are screw-shaped, positively charged, amphipathic molecules which exert their primary bactericidal action by the formation of pores in the cytoplasmic membrane (20). The type B lantibiotics, as defined so far (e.g., duramycin and cinnamycin), possess a globular shape, carry no net charge or a negative charge, and are described as inhibitors of phospholipase A 2 or the angiotensin-converting enzyme (3). Mersacidin does not completely conform to either group because of atypical structural features (9, 11).Here, we report that it is also different regarding its mode of bactericidal activity. We show that mersacidin inhibits peptidoglycan biosynthesis, probably on the level of transglycosylation. Furthermore, we demonstrate that on the molecular level its mode of action differs from those of glycopeptide antibiotics like vancomycin or teicoplanin. This opens the possibility of using a new target for the antibiotic treatment of methicillinresistant S. aureus strains and makes mersacidin an interesting tool for the investigation of peptidoglycan biosynthesis of gram-positive bacteria.
MATERIALS AND METHODSBacterial strains and growth conditions. Staphylococcus simulans 22 (formerly Staphylococcus cohnii 22; Institute for Medical Microbiology and Immunology of the University of Bonn, Bonn, ...