Daptomycin: Mechanism of Action and Bacterial Resistance

I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. ii Daptomycin is an important lipopeptide antibiotic used for treating severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus species. Its bactericidal activity requires calcium and the presence of phosphatidylglycerol (PG) in the target membrane and correlates with membrane depolarization. Daptomycin has also been shown to form oligomers on target membranes. Based on these findings, it has been proposed that the bactericidal effect of daptomycin arises from the formation of oligomeric pores or channels. This thesis reports experiments that test and further characterize this proposed mode of action. In the first project, reported in chapter 2, it is demonstrated that oligomer formation is nec-essary for the bactericidal effect. The semisynthetic lipopeptide CB-182,462, which is simila