Bioinformatics-driven discovery of novel Clostridioides difficile lysins and experimental comparison with highly active benchmarks.
Bioinformatics-driven discovery of novel Clostridioides difficile lysins and experimental comparison with highly active benchmarks.
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DOI：
10.1002/bit.27759
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发表时间：
2021-07
影响因子：
3.8
通讯作者：
Griswold, Karl E.
中科院分区：
文献类型：
--
作者：
Furlon, Jacob M.;Mitchell, Spencer J.;Bailey-Kellogg, Chris;Griswold, Karl E.
艰难梭菌是美国唯一最致命的细菌病原体，其全球流行和巨大的健康影响强调了对更有效治疗选择的需求。为了实现这一目标，一组新的修饰的肽聚糖水解酶具有显着的体外杀菌活性已成为治疗C。艰难梭菌感染（CDI）。迄今为止，针对这些CDI特异性溶素的发现和开发努力有限，特别是尚未对已知或新发现的溶素候选物进行系统比较。在这里，我们详细介绍了生物信息学驱动的六个新的抗C的发现。艰难梭菌溶素属于酰胺酶-3家族的酶，我们描述了它们各自的催化结构域（CAT）与来自文献的高活性CAT的实验比较。我们的定量分析包括表达水平，固有的抗菌活性，菌株选择性的广度，杀死发芽孢子，以及热稳定性的结构和功能措施的指标。重要的是，以前的研究没有检查稳定性作为性能指标，我们的结果表明，八种酶的面板具有广泛可变的热变性温度和耐热失活性，包括一些在体温下表现出边缘稳定性的酶。最终，没有一种酶在所有性能指标方面占主导地位，这表明在寻找、工程设计和开发具有真正临床潜力的候选物的过程中需要平衡评估溶素性质。
Clostridioides difficile is the single most deadly bacterial pathogen in the United States, and its global prevalence and outsized health impacts underscore the need for more effective therapeutic options. Towards this goal, a novel group of modified peptidoglycan hydrolases with significant in vitro bactericidal activity have emerged as potential candidates for treating C. difficile infections (CDI). To date, discovery and development efforts directed at these CDI-specific lysins have been limited, and in particular there has been no systematic comparison of known or newly discovered lysin candidates. Here, we detail bioinformatics-driven discovery of six new anti-C. difficile lysins belonging to the amidase-3 family of enzymes, and we describe experimental comparison of their respective catalytic domains (CATs) with highly active CATs from the literature. Our quantitative analyses include metrics for expression level, inherent antibacterial activity, breadth of strain selectivity, killing of germinating spores, and structural and functional measures of thermal stability. Importantly, prior studies have not examined stability as a performance metric, and our results show that the panel of eight enzymes possess widely variable thermal denaturation temperatures and resistance to heat inactivation, including some enzymes that exhibit marginal stability at body temperature. Ultimately, no single enzyme dominated with respect to all performance measures, suggesting the need for a balanced assessment of lysin properties during efforts to find, engineer, and develop candidates with true clinical potential.
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美国梭菌艰难梭菌感染和结果负担的趋势。
DOI：
10.1056/nejmoa1910215
发表时间：
2020-04-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guh AY;Mu Y;Winston LG;Johnston H;Olson D;Farley MM;Wilson LE;Holzbauer SM;Phipps EC;Dumyati GK;Beldavs ZG;Kainer MA;Karlsson M;Gerding DN;McDonald LC;Emerging Infections Program Clostridioides difficile Infection Working Group
通讯作者：
Emerging Infections Program Clostridioides difficile Infection Working Group
影响因子：
3.4
作者：
Lee YY;Erdogan A;Rao SS
通讯作者：
Rao SS
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W
影响因子：
4.4
作者：
Mehta, Krunal K.;Paskaleva, Elena E.;Kane, Ravi S.
通讯作者：
Kane, Ravi S.