13-deoxytetrodecamycin and Thamamycin: Two Promising Tetrodecamycin Antibiotics

Abstract

Antibiotic-resistant bacteria pose a serious threat to modern medicine. Methicillin-resistant Staphylococcus aureus (MRSA) is among the most alarming pathogens due to its prevalence in hospitals and the community and the emergence of multi-drug resistant isolates. 13-deoxytetrodecamycin (13-dTDM) and thamamycin (THM) are novel, related members of the tetrodecamycin antibiotic class that are bioactive against MRSA. Presently, their targets and mode of action are unknown although their structural novelty and potency against drug-resistant bacteria makes them very attractive subjects for research. The aim of this thesis was to increase the yield of 13-dTDM and THM in order to elucidate their molecular target and mode of action. Utilizing a ‘ribosome engineering’ approach, I have successfully increased the yield of THM. I also demonstrate that 13-dTDM and THM are bactericidal and do not target the lipid II cycle of cell wall biosynthesis. Lastly, preliminary data suggests possible targeting of the folate pathway by THM.