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由Photorhabdus产生的小分子干扰了格拉姆阴性细菌中乌比金生物合成

Rachel Bargabos¹, Akira Iinishi¹, Bryson Hawkins¹

¹Antimicrobial Discovery Center, Northeastern University, Boston, Massachusetts, USA.

|September 10, 2024

概括

一种新型抗生素,3,6-二基-1,2-二佐 (DHB),通过抑制乌比金生物合成并充当前药物来向格兰阴性细菌. 这一发现提供了一种双重作用的化合物来打击抗菌素耐药性危机.

科学领域:

微生物学微生物学
生物化学生物化学
药物发现药物发现药物发现

背景情况:

抗菌素耐药性的上升需要开发新的抗生素,特别是针对格拉姆阴性病原体.
线虫和像Photorhabdus这样的细菌之间的共生关系提供了具有潜在抗菌性能的新型二次代谢物的来源.

研究的目的:

为了识别和描述来自*Photorhabdus*共生体的新型抗菌化合物.
为了阐明已识别的化合物3,6-二基-1,2-二佐 (DHB) 的作用机制和选择性.

主要方法:

对*Photorhabdus*和*Xenorhabdus*的细菌共生体进行抗菌活性查.
确定针对格拉姆阴性细菌的活性谱.
对抗性突变的遗传映射以确定目标途径.
使用4-基酸八烯转移酶 (UbiA) 的酶抑制试验.

主要成果:

鉴定3,6-二基-1,2-二佐 (DHB) 具有针对格拉姆阴性细菌 (*大肠杆菌,E.cloacae,K.pneumoniae,A.baumannii*) 的选择性活性.
DHB通过向UbiA酶来抑制乌比昆生物合成,从而防止4-基-3-八烯基酸盐的形成.
DHB作为一种前药物,被UbiA先化成一种有毒的化学产品,有助于其抗菌作用.
抵抗突变映射到ubiquinone生物合成途径,而DHB选择性与UbiA酶的结构有关.

结论:

DHB表现出独特的双重作用模式,既是一种酶抑制剂,又是一种前药物.
发现DHB提供了一个有前途的化合物,用于开发新的抗生素来对抗具有挑战性的阴性病原体.
了解DHB-UbiA相互作用机制为新型抗微生物战略提供了洞察力.

关键词:

格拉姆阴性细菌是一种细菌.抗生素耐药性抗生素耐药性天然抗微生物产品天然抗微生物产品.

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