I) Characterization of LytR-CpsA-Psr enzymes and their role in <em>Staphylococcus aureus</em> cell wall formation <br>II) Elucidating the mode of action of Cacaoidin, a novel class V lantibiotic

Abstract

Antibiotic resistance poses a serious threat to human health, demanding for the discovery and development of antibiotics with resistance-breaking properties. New antibiotics should be sought with the focus on novel chemistry and mechanisms of actions. Furthermore, a profound understanding of the antibiotic target, in the biological context as well as on a cellular level, the target-antibiotic interaction, and the cellular consequences of antibiotic treatment is necessary.<br /> This work is divided in two major parts. The first part encloses the complete in vitro reconstitution of the capsule assembly in Staphylococcus aureus as well as the identification and characterization of regulatory circuits which coordinate capsule assembly and peptidoglycan synthesis. Furthermore, LcpC a member of the LytR-CpsA-Psr (LCP) protein family was demonstrated to catalyze the previously elusive attachment of capsular polysaccharides to the cell wall and the peptidoglycan precursor lipid II was identified as the acceptor substrate. The detailed characterization of the LcpC catalyzed reaction further provided the foundation to screen for inhibitors. The second part of this work describes the discovery and elucidation of the mechanism of action of the lantibiotic cacaoidin.