As drug-resistant pathogens pose an increasing threat to human health worldwide, there is a need for new antibacterial compounds with novel and selective targets. Plantazolicin (PZN) is a ribosomally produced peptide with extensive posttranslational modifications that exhibits exquisite antibacterial selectivity for Bacillus anthracis, the causative agent of anthrax, suggesting a species-specific and novel mechanism of action. In order to determine its molecular target, a structure-activity relationship study of PZN was initiated to identify moieties essential for bioactivity. Synthetically prepared truncations of the polyazole core of PZN displayed broader-spectrum antibacterial activity but were less potent than the full-length natural product, suggesting the cruciality of the polyheterocyclic core for bioactivity. Based on the ability to modify the C-terminus of PZN without significantly affecting bioactivity, biotinylated and fluorescently labeled derivatives of PZN were prepared. These probes are being employed in affinity purification and fluorescence microscopy to demonstrate the unique mechanism of action of PZN. 

Investigation of the mechanism of action of a species-selective antibacterial compound

248th National Meeting (2014)

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