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

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The Polyene Natural Product Thailandamide A Inhibits Fatty Acid Biosynthesis in Gram-Positive and Gram-Negative Bacteria
Biochemistry ( IF 2.9 ) Pub Date : 2018-07-05 00:00:00 , DOI: 10.1021/acs.biochem.8b00678
Yihan Wu ₁ , Mohammad R. Seyedsayamdost _{1,

2}

Affiliation

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.

中文翻译：

多烯天然产物泰国酰胺A抑制革兰氏阳性细菌和革兰氏阴性细菌中的脂肪酸生物合成。

Burkholderia thailandensis产生大量令人印象深刻的次级代谢产物，大多数具有未知目标。这些代谢物之一是泰国酰胺，这是一种线性多烯天然产物，由相应的tha基因簇组成性合成。使用广泛的生物活性筛选，我们观察到泰国酰胺对革兰氏阳性和细胞壁弱化的革兰氏阴性细菌具有强而选择性的抗菌活性。细菌细胞学分析以及与10种具有已知作用方式的抗生素的比较显示出Thaitamamide的独特特征，表明其独特的抑制机制。为了解决该药物的目标，我们获得了枯草芽孢杆菌的抗性突变体，并将抗性表型映射到accA，其产物催化脂肪酸生物合成的第一步。有趣的是，tha基因簇编码具有相似氨基酸取代的accA同源物。异源表达表明，它赋予了对原本易感的大肠杆菌培养物的抗性，表明它对产生泰国酰胺的泰国芽孢杆菌细胞具有免疫力。除了moiramide B和andrimid，thailandamide仅代表通过靶向AccA / AccD抑制细菌生长的第二类天然产物。

更新日期：2018-07-05

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