In vivo evaluation of Clostridioides difficile enoyl-ACP reductase II (FabK) Inhibition by phenylimidazole unveils a promising narrow-spectrum antimicrobial strategy.
In vivo evaluation of Clostridioides difficile enoyl-ACP reductase II (FabK) Inhibition by phenylimidazole unveils a promising narrow-spectrum antimicrobial strategy.
复制标题
对苯基咪唑对艰难梭菌烯酰-ACP 还原酶 II (FabK) 抑制作用的体内评估揭示了一种有前景的窄谱抗菌策略。
DOI：
10.1101/2023.09.22.559005
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hurdle,JulianG
中科院分区：
文献类型：
--
作者：
Dureja,Chetna;Rutherford,JacobT;Pavel,FahadBA;Norseeda,Krissada;Prah,Isaac;Sun,Dianqing;Hevener,KirkE;Hurdle,JulianG
艰难梭菌感染（CDI）是医院获得性腹泻的主要原因，通常源于广谱抗生素对肠道微生物群的破坏。抗生素耐药性日益普遍。艰难梭菌，再加上最近候选抗生素的临床试验结果令人失望，强调了对新型CDI抗生素的迫切需要。为此，我们调查了c。艰难绿烯酰基ACP还原酶（CdFabK）是新脂肪酸合成的关键酶，作为微生物组保护抗生素的药物靶点。为了验证这一概念，我们评估了苯咪唑类似物296的功效和体内活性，证实其抑制细胞内的arcdfabk。296对主要cdi相关核型的最低抑制浓度（MIC90）为2µg/mL，与标准护理抗生素万古霉素（1µg/mL）相当。此外，296在结肠炎CDI小鼠中达到高结肠浓度并表现出剂量依赖的疗效。给予296的小鼠保留了对c的定植抗性。艰难梭菌的微生物组与未治疗的小鼠相似。相反，万古霉素和非达霉素都能诱导小鼠微生物组发生显著变化，这与先前的报道一致。因此，CdFabK代表了保留微生物组的CDI抗生素的潜在靶标，苯基咪唑为设计此类药物提供了良好的化学起点。
Clostridioides difficileinfection (CDI) is a leading cause of hospital-acquired diarrhea, which often stems from disruption of the gut microbiota by broad-spectrum antibiotics. The increasing prevalence of antibiotic-resistantC. difficilestrains, combined with disappointing clinical trial results for recent antibiotic candidates, underscores the urgent need for novel CDI antibiotics. To this end, we investigatedC. difficileenoyl ACP reductase (CdFabK), a crucial enzyme inde novofatty acid synthesis, as a drug target for microbiome-sparing antibiotics. To test this concept, we evaluated the efficacy andin vivospectrum of activity of the phenylimidazole analog 296, which is validated to inhibit intracellularCdFabK. Against major CDI-associated ribotypes 296 had an Minimum inhibitory concentration (MIC90) of 2 µg/mL, which was comparable to vancomycin (1 µg/mL), a standard of care antibiotic. In addition, 296 achieved high colonic concentrations and displayed dosed-dependent efficacy in mice with colitis CDI. Mice that were given 296 retained colonization resistance toC. difficileand had microbiomes that resembled the untreated mice. Conversely, both vancomycin and fidaxomicin induced significant changes to mice microbiomes, in a manner consistent with prior reports.CdFabK, therefore, represents a potential target for microbiome-sparing CDI antibiotics, with phenylimidazoles providing a good chemical starting point for designing such agents.