Baulamycin A & B: In vitro Siderophore Biosynthesis Inhibitors with a Newly Discovered Mechanism
Bacteria in nutrient-rich conditions typically do not reflect the environment and behaviors that they exhibit within a human host. Iron is a nutrient in particular that is typically abundant in a laboratory setting, but the concentration of free iron within a human host is extremely low due to iron transport and storage systems that have been tailored by evolution. Therefore, inhibition of bacterial iron acquisition is a novel strategy to combat pathogenic bacteria within a human host. To this end, the baulamycins were discovered and shown to inhibit bacterial iron acquisition in vitro via inhibition of the biosynthesis of iron-chelating siderophores. In addition to in vitro inhibition, the compounds were shown to possess broad-spectrum inhibitory activity in iron-rich media. This led us to believe that the compounds were operating by more than one mode of action.
After synthesis of the natural products, we synthesized 8 rationally designed analogs in order to test specific hypotheses about the compounds’ mode of action. We discovered that, in the case of Staphylococcus aureus, the baulamycins induced membrane damage, which explained their broad-spectrum inhibitory activity. Unfortunately, our most potent analogs also induced hemolysis. Current and future work is aimed further optimizing the scaffolds for bacterial membrane selectivity and potency.
Steele, A.D.; Ernouf, G.; Lee, Y-E.; Wuest, W.M.* “Diverted Total Synthesis of the Baulamycins and Analogues Reveals an Alternate Mechanism of Action” Organic Letters 2018 20, 1126 DOI: 10.1021/acs.orglett.8b00054