Synthesis and Antibacterial Activity of Propylamycin Derivatives Functionalized at the 5''- and Other Positions with a View to Overcoming Resistance Due to Aminoglycoside Modifying Enzymes.
Synthesis and Antibacterial Activity of Propylamycin Derivatives Functionalized at the 5''- and Other Positions with a View to Overcoming Resistance Due to Aminoglycoside Modifying Enzymes.
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DOI：
10.1021/acsinfecdis.1c00158
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发表时间：
2021-08-13
影响因子：
5.3
通讯作者：
Crich D
中科院分区：
文献类型：
--
作者：
Lubriks D;Zogota R;Sarpe VA;Matsushita T;Sati GC;Haldimann K;Gysin M;Böttger EC;Vasella A;Suna E;Hobbie SN;Crich D
Propylamycin（4'-脱氧-4'-丙基巴龙霉素）是新一代氨基糖苷类抗生素，在豚鼠模型中显示出比母体更高的抗菌效力，同时降低了对耐药决定因素的敏感性并降低了耳毒性。然而，丙霉素会被 APH(3’)-Ia 灭活，APH(3’)-Ia 是一种特定的氨基糖苷磷酸转移酶同工酶，作用于呋喃核糖基部分（5”位）的伯羟基。为了克服这个问题，我们制备并研究了各种在 5”位携带氨基或取代氨基取代脆弱羟基的丙霉素衍生物的抗菌和抗核糖体活性。我们发现，在该位置引入额外的碱性氨基，同时克服了预期的作用于 5” 位的氨基糖苷磷酸转移酶同工酶的作用，导致细菌相对于真核核糖体的选择性显着下降，这预示着耳毒性增加。相比之下，5”-脱氧-5”-甲酰胺丙基霉素保留了丙霉素优异的全面抗菌活性水平其本身，同时规避了有害的氨基糖苷类磷酸转移酶同工酶的作用，并为细菌提供了比真核核糖体更高的选择性。解决丙霉素对 APH(3')-Ia 同工酶敏感性的其他修饰，包括 3' 位脱氧和掺入 6',5"-双（羟乙基氨基）修饰，没有提供特别的优势。概要：TOC 图显示了最佳化合物的结构，其中两个关键特征用绿色强调。
Propylamycin (4’-deoxy-4’-propylparomomycin) is a next generation aminoglycoside antibiotic that displays increased antibacterial potency over the parent, coupled with reduced susceptibility to resistance determinants and reduced ototoxicity in the guinea pig model. Propylamycin nevertheless is inactivated by APH(3’)-Ia, a specific aminoglycoside phosphotransferase isozyme that acts on the primary hydroxy group of the ribofuranosyl moiety (at the 5”-position). To overcome this problem we have prepared and studied the antibacterial and antiribosomal activity of various propylamycin derivatives carrying amino or substituted amino groups at the 5”-position in place of the vulnerable hydroxy group. We find that the introduction of an additional basic amino group at this position, while overcoming the action of the aminoglycoside phosphoryltransferase isozymes acting at the 5”-position as anticipated, results in a significant drop in selectivity for the bacterial over the eukaryotic ribosomes that is predictive of increased ototoxicity. In contrast, 5”-deoxy-5”-formamidopropylamycin retains the excellent across-the-board levels of antibacterial activity of propylamycin itself, while circumventing the action of the offending aminoglycoside phosphotransferase isozymes, and affording even greater selectivity for the bacterial over the eukaryotic ribosomes. Other modifications to address the susceptibility of propylamycin to the APH(3’)-Ia isozyme including deoxygenation at the 3’-position and incorporation of a 6’,5”-bis(hydroxyethylamino) modification offer no particular advantage. Synopsis: The TOC graphic shows the structure of the optimal compound with the two key features colored green for emphasis.
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改进的 4'-O-（烷基）4,5-二取代 2-脱氧链霉胺作为下一代氨基糖苷类抗生素的鉴定和评估。
影响因子：
6.4
作者：
Duscha S;Boukari H;Shcherbakov D;Salian S;Silva S;Kendall A;Kato T;Akbergenov R;Perez-Fernandez D;Bernet B;Vaddi S;Thommes P;Schacht J;Crich D;Vasella A;Böttger EC
通讯作者：
Böttger EC
DOI：
10.1007/978-1-4614-1400-1_7
发表时间：
2012-01-01
期刊：
ANTIBIOTIC DISCOVERY AND DEVELOPMENT, VOLS 1 AND 2
影响因子：
--
作者：
Armstrong, Eliana S.;Kostrub, Corwin F.;Miller, George H.
通讯作者：
Miller, George H.
氨基糖苷与解码位点寡核苷酸之间的复合物的晶体结构：环数和正电荷在特定结合中导致错误编码的作用。
影响因子：
14.9
作者：
François, B;Russell, RJM;Murray, JB;Aboul-ela, F;Masquida, B;Vicens, Q;Westhof, E
通讯作者：
Westhof, E
影响因子：
5.3
作者：
Jiang M;Karasawa T;Steyger PS
通讯作者：
Steyger PS
影响因子：
64.5
作者：
Brodersen, DE;Clemons, WM;Ramakrishnan, V
通讯作者：
Ramakrishnan, V