Due to the rise and global proliferation in drug-resistant bacterial infections, we face a continuing need to have a supply of novel antibacterial agents that are not just more potent or useful against a broader spectrum of organisms, but are structurally distinct from current compounds. One benefit of identifying antibacterial compounds with novel structures includes the potential to circumvent current resistance mechanisms by inhibiting new essential targets. Natural products have a long history of being useful as drugs and inhibitors, and marine natural products offer additional benefits because the unique compounds of the marine environment often have no terrestrial analogs; a higher percentage of bioactive compounds are found in marine organisms; and bioactive agents can be detected and isolated directly without the need for culture. The work presented in this dissertation describes the isolation and identification of two diverse structural classes of antibacterial agents from a marine sponge and a marine chrysophyte alga. Both classes of compounds inhibit drug-susceptible and drug-resistant Gram-positive organisms. The work with the first class of compounds, termed the motualevic acids, describes the biological activity of both natural product compounds and synthetic analogs. The work on the second class of compounds, named the chrysophaentins, describes the biological activity of the natural compounds and synthetic fragments, the geographic variability in the production of the natural chrysophaentins by the source alga, and the mechanism of action of the chrysophaentins. This work shows that the chrysophaentins prevent bacterial cell division through inhibition of the prokaryotic cytoskeletal protein, FtsZ. The details of the mechanism and the mode of inhibition of the chrysophaentins are further described in the context of other commercially available FtsZ inhibitors. This body of work contributes to the field of marine natural products chemistry by disclosing novel antibacterial agents, and heightens our understanding of the broader picture of FtsZ inhibitors and the inhibition of FtsZ as an antimicrobial target.
|Advisor:||Bewley, Carole A.|
|Commitee:||Banerjee, Partha, Brown, Milton, Cihlar, Ron, Roepe, Paul D., Vasudevan, Sona|
|Department:||Biochemistry & Molecular|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 74/02(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Biochemistry, Organic chemistry|
|Keywords:||Antimicrobials, Ftsz, Marine natural products, Marine-derived antibacterial compounds, Pharmacognosy|
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