Functional and Metagenomic Evaluation of Ibezapolstat for Early Evaluation of Anti-Recurrence Effects in Clostridioides difficile Infection.
Functional and Metagenomic Evaluation of Ibezapolstat for Early Evaluation of Anti-Recurrence Effects in Clostridioides difficile Infection.
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DOI：
10.1128/aac.02244-21
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发表时间：
2022-08-16
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
减少艰难梭菌感染（CDI）复发是CDI导向抗生素开发的一个重要终点，通常在III期试验之前不会进行评估。该项目的目的是使用功能和宏基因组方法来预测ibezapolstat（一种DNA聚合酶IIIC抑制剂）在CDI临床开发中的潜在抗CDI复发作用。作为I期ibezapolstat临床研究的一部分，从给予ibezapolstat或万古霉素的22名健康志愿者收集粪便样品。评价粪便样品的微生物组变化和胆汁酸浓度。与安慰剂相比，伊贝扎泊他450 mg和万古霉素（但不是伊贝扎泊他300 mg）显示α多样性随时间的统计学显著变化。β多样性变化证实了研究组之间的微生物群存在显著差异。万古霉素对微生物组有更广泛的影响，其特征是γ-变形菌的比例增加。伊贝扎泊司他显示放线菌的比例增加，包括双歧杆菌科。使用线性回归分析，万古霉素与原发性胆汁酸以及原发性：继发性胆汁酸比值显著增加相关。肠杆菌科细菌的丰度与初级胆汁酸浓度的相关性最高（r = 0.63; P <0.0001）。使用I期健康志愿者样本，与万古霉素相比，ibezapolstat与提示CDI复发风险较低的有益变化相关。这种新的组学方法可以更好地和更早地预测临床开发管道中抗生素的抗CDI复发作用。
Reduction of Clostridioides difficile infection (CDI) recurrence is an essential endpoint for CDI-directed antibiotic development that is often not evaluated until Phase III trials. The purpose of this project was to use a functional and metagenomic approach to predict the potential anti-CDI recurrence effect of ibezapolstat, a DNA polymerase IIIC inhibitor, in clinical development for CDI. As part of the Phase I ibezapolstat clinical study, stool samples were collected from 22 healthy volunteers, who were given either ibezapolstat or vancomycin. Stool samples were evaluated for microbiome changes and bile acid concentrations. Ibezapolstat 450 mg and vancomycin, but not ibezapolstat 300 mg, showed statistically significant changes in alpha diversity over time compared to that of a placebo. Beta diversity changes confirmed that microbiota were significantly different between study groups. Vancomycin had a more wide-ranging effect on the microbiome, characterized by an increased proportion of Gammaproteobacteria. Ibezapolstat demonstrated an increased proportion of Actinobacteria, including the Bifidobacteriaceae family. Using a linear regression analysis, vancomycin was associated with significant increases in primary bile acids as well as primary:secondary bile acid ratios. An overabundance of Enterobacteriaceae was most highly correlated with primary bile acid concentrations (r = 0.63; P < 0.0001). Using Phase I healthy volunteer samples, beneficial changes suggestive of a lower risk of CDI recurrence were associated with ibezapolstat compared to vancomycin. This novel omics approach may allow for better and earlier prediction of anti-CDI recurrence effects for antibiotics in the clinical development pipeline.
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影响因子：
64.8
作者：
Stewart CJ;Ajami NJ;O'Brien JL;Hutchinson DS;Smith DP;Wong MC;Ross MC;Lloyd RE;Doddapaneni H;Metcalf GA;Muzny D;Gibbs RA;Vatanen T;Huttenhower C;Xavier RJ;Rewers M;Hagopian W;Toppari J;Ziegler AG;She JX;Akolkar B;Lernmark A;Hyoty H;Vehik K;Krischer JP;Petrosino JF
通讯作者：
Petrosino JF
影响因子：
2.3
作者：
Gonzales-Luna AJ;Spinler JK;Oezguen N;Khan MAW;Danhof HA;Endres BT;Alam MJ;Begum K;Lancaster C;Costa GP;Savidge TC;Hurdle JG;Britton R;Garey KW
通讯作者：
Garey KW
影响因子：
11.8
作者：
Johnson, Stuart;Lavergne, Valery;Wilcox, Mark H.
通讯作者：
Wilcox, Mark H.
影响因子：
4.2
作者：
Boix, Vicente;Fedorak, Richard N.;Murata, Yoshihiko
通讯作者：
Murata, Yoshihiko
影响因子：
82.9
作者：
Taur Y;Pamer EG
通讯作者：
Pamer EG