In 2016, the cahuitamycins, a new group of natural products, were discovered through a screen of natural product extracts. These molecules were shown to selectively inhibit biofilm growth in <i>Acinetobacter baumannii</i>, a Gram-negative ESKAPE pathogen, with minimal effect on planktonic growth. The active compounds contain canonical siderophore iron-chelating moieties, including a phenolate-oxazoline and a hydroxamate. They also contain an unusual piperazate residue that has rarely been observed in other natural products. We have recently completed the first total synthesis of the reported parent compound, cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Biological evaluation and extensive NMR analysis revealed key differences between the synthetic cahuitamycin A and the authentic sample. Based on these findings, we synthesized four structural isomers, all of which do not match the spectral data for the isolated compound. Ongoing efforts include the synthesis additional isomers in order to elucidate the true natural product structure and use this class of molecules to investigate the interplay between iron homeostasis and biofilm formation.

Total synthesis of the reported structure of cahuitamycin A and isomers

ACS Fall 2021

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