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Lantibiotics
Lantibiotics (lanthionine containing antibiotics) are ribosomally synthesized peptides with antibacterial activity. The rare amino acids, e. g. the thioether forming lanthionines, are synthesized by characteristic modification enzymes that are encoded in the vicinity of the structural genes in biosynthetic gene clusters. All lantibiotics described so far are produced by and active against Gram-positive bacteria.
Our focus is the analysis of novel lantibiotics from sequenced genomes. In the last years a multitude of bacterial genomes has been sequenced. Sequence analyses in the data banks have shown that open reading frames with similarity to lantibiotic modification enzymes are present in many bacterial phylae as cyanobacteria and proteobacteria. These novel lantibiotics are interesting for us, since they may well represent blueprints for new chemotherapeutics.
Mersacidin is a lantibiotic that has been in the focus or our research for some years. It kills sensitive cells by inhibiting cell wall biosynthesis. Staphylococci are among the sensitive organisms. Mersacidin binds to the extracellular cell wall precursor lipid II and is also active against MRSA (methicillin resistant staphylococci). The producer of mersacidin is a Bacillus strain. We have sequenced the biosynthetic gene cluster of mersacidin. At the moment we are interested in the regulation of mersacidin biosynthesis and the mechanism that confers self protection of the producer strain. Additionally, a system for site directed engineering of mersacidin has been established.
Molecular mechanisms of the antibiotic resistance in Staphylococcus aureus
Staphylococcus aureus is one of the most prominent infectious agents and causes mainly nosocomial disease. The emergence of methicillin resistant strains (MRSA) in the hospitals and in the community is a growing problem. Infections with MRSA strains are treated with vancomycin or newer chemotherapeutics like synercid, daptomycin and linezolid. Strains with intermediate or high resistance to vancomycin have been isolated in the last years. We have characterized a strain pair showing intermediate resistance to vancomycin and it seems that mutations in a regulatory two component system and inactivation of a membrane protein, decreased cross linking of the cell wall as well as increased cell wall and capsule formation lead to this phenotype. Furthermore, we are studying other antibiotics that target lipid II and the resistance strategies that the bacteria have evolved against these antibiotics. Another focus of our work is a laboratory mutant, that displays a high level of vancomycin resistance.
Additionally, we are interested in the relationship between environmental stress and the development of antibiotic resistance in staphylococci. Possible mechanisms are the mobilisation of IS-elements, transposons etc. or point mutations, which may be caused by an increased mutation frequency.
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