The Polyene Natural Product Thailandamide A Inhibits Fatty Acid Biosynthesis in Gram-Positive and Gram-Negative Bacteria.

TitleThe Polyene Natural Product Thailandamide A Inhibits Fatty Acid Biosynthesis in Gram-Positive and Gram-Negative Bacteria.
Publication TypeJournal Article
Year of Publication2018
AuthorsWu, Y, Seyedsayamdost, MR
JournalBiochemistry
Volume57
Issue29
Pagination4247-4251
Date Published2018 Jul 24
ISSN1520-4995
Abstract

Burkholderia thailandensis produces an impressive array of secondary metabolites, most with yet unknown targets. One of these metabolites is thailandamide, a linear polyene natural product that is constitutively synthesized by the corresponding tha gene cluster. Using broad bioactivity screens, we observed strong yet selective antibacterial activity by thailandamide against Gram-positive and cell wall-weakened Gram-negative bacteria. Bacterial cytological profiling and comparison with 10 antibiotics with known modes of action revealed a unique profile for thailandamide, suggesting a distinct mechanism of inhibition. To address the target of the drug, we obtained resistant mutants of Bacillus subtilis and mapped the resistant phenotype to accA, the product of which catalyzes the first committed step in fatty acid biosynthesis. Interestingly, the tha gene cluster encodes an accA homologue with a similar amino acid substitution. Heterologous expression showed that it confers resistance to otherwise susceptible Escherichia coli cultures, indicating that it provides immunity to thailandamide-producing B. thailandensis cells. Aside from moiramide B and andrimid, thailandamide represents only the second class of natural products that inhibits bacterial growth by targeting AccA/AccD.

DOI10.1021/acs.biochem.8b00678
Alternate JournalBiochemistry
PubMed ID29975047