我们报告了在光性横纹肌和Xenorhabdus屏幕中3,6-二羟基-1,2-苯并异恶唑(DHB)的鉴定,其与真核线虫的共生关系有利于次生代谢产物,这些代谢产物满足与临床上有用的抗生素相匹配的几个要求。DHB由Laumondii产生,对革兰氏阴性大肠杆菌具有选择性,阴沟肠杆菌,粘质沙雷菌,肺炎克雷伯菌,变形杆菌,和鲍曼不动杆菌.它对厌氧肠道细菌无活性,对人细胞无毒。对DHB具有抗性的突变体映射到泛醌生物合成途径。DHB与4-羟基苯甲酸酯八苯乙烯基转移酶(UbiA)结合,并阻止4-羟基-3-八苯乙烯苯甲酸酯的形成。值得注意的是,DHB本身是戊烯化的,形成不可用的嵌合产物,这可能有助于这种抗菌剂的毒性作用。DHB似乎既是竞争性酶抑制剂又是前药;这种双重作用模式对于抗微生物化合物而言是不寻常的。
目的:耐药病原菌的传播导致了抗菌药物的耐药危机,并且对新化合物的需要对革兰氏阴性病原体起作用是特别迫切的。从线虫的光生共生体的屏幕上,我们鉴定了3,6-二羟基-1,2-苯并异恶唑(DHB),可对抗一系列革兰氏阴性细菌,包括大肠杆菌,阴沟肠杆菌,肺炎克雷伯菌,和鲍曼不动杆菌.DHB以前是从其他细菌物种中分离出来的,但其作用机制仍然未知。我们证明DHB在抗菌药物中是独一无二的,具有作为重要酶抑制剂的双重作用,乌比,在泛醌的生物合成途径和作为前药。DHB是天然底物的模拟物,UbiA将它变成有毒产品,有助于这种不寻常的抗生素的抗菌作用。我们还揭示了DHB选择性的机制,这取决于UbiA酶的特定折叠。
We report the identification of 3,6-dihydroxy-1,2-benzisoxazole (DHB) in a screen of Photorhabdus and Xenorhabdus, whose symbiotic relationship with eukaryotic nematodes favors secondary metabolites that meet several requirements matching those for clinically useful antibiotics. DHB is produced by Photorhabdus laumondii and is selective against the Gram-negative species Escherichia coli, Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis, and Acinetobacter baumannii. It is inactive against anaerobic gut bacteria and nontoxic to human cells. Mutants resistant to DHB map to the ubiquinone biosynthesis pathway. DHB binds to 4-hydroxybenzoate octaprenyltransferase (UbiA) and prevents the formation of 4-hydroxy-3-octaprenylbenzoate. Remarkably, DHB itself is prenylated, forming an unusable chimeric product that likely contributes to the toxic effect of this antimicrobial. DHB appears to be both a competitive enzyme inhibitor and a prodrug; this dual mode of action is unusual for an antimicrobial compound.
OBJECTIVE: The spread of resistant pathogens has led to the antimicrobial resistance crisis, and the need for new compounds acting against Gram-negative pathogens is especially acute. From a screen of Photorhabdus symbionts of nematodes, we identified 3,6-dihydroxy-1,2-benzisoxazole (DHB) that acts against a range of Gram-negative bacteria, including Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Acinetobacter baumannii. DHB had previously been isolated from other bacterial species, but its mechanism of action remained unknown. We show that DHB is unique among antimicrobials, with dual action as an inhibitor of an important enzyme, UbiA, in the biosynthesis pathway of ubiquinone and as a prodrug. DHB is a mimic of the natural substrate, and UbiA modifies it into a toxic product, contributing to the antimicrobial action of this unusual antibiotic. We also uncover the mechanism of DHB selectivity, which depends on a particular fold of the UbiA enzyme.