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Discovery of Novel Antibiotics as Covalent Inhibitors of Fatty Acid Synthesis.
ACS Chemical Biology ( IF 4 ) Pub Date : 2020-06-22 , DOI: 10.1021/acschembio.9b00982
Jia Wang 1 , Xiaoping Ye 1 , Xiaohan Yang 1 , Youyan Cai 1 , Shengjun Wang 1 , Jieyu Tang 1 , Meena Sachdeva 2 , Yu Qian 1 , Wenhao Hu 1 , Jennifer A Leeds 2 , Yanqiu Yuan 1, 3
Affiliation  

The steady increase in the prevalence of multidrug-resistant Staphylococcus aureus has made the search for novel antibiotics to combat this clinically important pathogen an urgent matter. In an effort to discover antibacterials with new chemical structures and mechanisms, we performed a growth inhibition screen of a synthetic library against S. aureus and discovered a promising scaffold with a 1,3,5-oxadiazin-2-one core. These compounds are potent against both methicillin-sensitive and methicillin-resistant S. aureus strains. Isolation of compound-resistant strains followed by whole genome sequencing revealed its cellular target as FabH, a key enzyme in bacterial fatty acid synthesis. Detailed mechanism of action studies suggested the compounds inhibit FabH activity by covalently modifying its active site cysteine residue with high selectivity. A crystal structure of FabH protein modified by a selected compound Oxa1 further confirmed covalency and suggested a possible mechanism for reaction. Moreover, the structural snapshot provided an explanation for compound selectivity. On the basis of the structure, we designed and synthesized Oxa1 derivatives and evaluated their antibacterial activity. The structure–activity relationship supports the hypothesis that noncovalent recognition between compounds and FabH is critical for the activity of these covalent inhibitors. We believe further optimization of the current scaffold could lead to an antibacterial with potential to treat drug-resistant bacteria in the clinic.

中文翻译:

发现新型抗生素作为脂肪酸合成的共价抑制剂。

耐多药金黄色葡萄球菌的患病率稳定增加,寻找新的抗生素来对抗这种临床上重要的病原体成为当务之急。为了发现具有新化学结构和机理的抗菌剂,我们对金黄色葡萄球菌进行了合成文库的生长抑制筛选,并发现了具有1,3,5-恶二嗪-2-one核心的有前途的支架。这些化合物对耐甲氧西林和耐甲氧西林的金黄色葡萄球菌均有效株。分离出具有抗药性的菌株,然后进行全基因组测序,揭示出其细胞靶标为FabH,它是细菌脂肪酸合成中的关键酶。详细的作用机理研究表明,这些化合物通过以高选择性共价修饰其活性位点半胱氨酸残基来抑制FabH活性。被选择的化合物Oxa1修饰的FabH蛋白的晶体结构进一步证实了共价性,并提出了可能的反应机理。此外,结构快照提供了化合物选择性的解释。在结构的基础上,我们设计和合成了Oxa1衍生物并评估了其抗菌活性。结构与活性之间的关系支持以下假设:化合物与FabH之间的非共价识别对于这些共价抑制剂的活性至关重要。我们认为,对当前支架的进一步优化可能会导致产生一种抗菌药,并有望在临床上治疗耐药菌。
更新日期:2020-07-17
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