Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens.
Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens.
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DOI：
10.1021/acs.jmedchem.2c01349
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发表时间：
2022-10-27
影响因子：
7.3
通讯作者：
Duerfeldt, Adam S.
中科院分区：
文献类型：
--
作者：
Hu, Ziwei;Leus, Inga V.;Chandar, Brinda;Sherborne, Bradley S.;Avila, Quentin P.;Rybenkov, Valentin V.;Zgurskaya, Helen I.;Duerfeldt, Adam S.
利奈唑胺治疗革兰氏阳性菌感染的临床成功与细菌核糖体的高度保守性相结合，预测如果恶唑烷酮被工程化以在革兰氏阴性菌中蓄积，则这种药理学类别将在根除感染中发现广泛的用途。在这里，我们报告了一个战略性设计的恶唑烷酮库的调查研究，以确定积累和生物活性的分子结构的影响。大肠埃希菌，鲍曼不动杆菌，铜绿假单胞菌菌株与不同程度的妥协（外排和外膜）被用来确定图案，阻碍通过外膜渗透和/或增强外排敏感性广泛和具体的物种之间。结果表明，分子结构的微小变化足以克服该支架的流出和/或渗透问题。鉴别出三种恶唑烷酮类似物（3e、8d和8 o）对评估的所有三种病原体均表现出活性，利奈唑胺未观察到生物学特征。
The clinical success of linezolid for treating Grampositive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.
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影响因子：
16
作者：
Leach, Karen L.;Swaney, Steven M.;Mankin, Alexander S.
通讯作者：
Mankin, Alexander S.
鉴定体内沙门氏菌鼠伤寒必不可少的代谢途径。
影响因子：
3.7
作者：
Jelsbak L;Hartman H;Schroll C;Rosenkrantz JT;Lemire S;Wallrodt I;Thomsen LE;Poolman M;Kilstrup M;Jensen PR;Olsen JE
通讯作者：
Olsen JE
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
2.7
作者：
Li, Yangxiong;Gardner, Jessi J.;Duerfeldt, Adam S.
通讯作者：
Duerfeldt, Adam S.
影响因子：
4.9
作者：
Krishnamoorthy, Ganesh;Wolloscheck, David;Zgurskaya, Helen I.
通讯作者：
Zgurskaya, Helen I.