An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity.
An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity.
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DOI：
10.1002/cmdc.202000726
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发表时间：
2021-01-19
期刊：
影响因子：
3.4
通讯作者：
Crich D
中科院分区：
文献类型：
--
作者：
Sonousi A;Quirke JCK;Waduge P;Janusic T;Gysin M;Haldimann K;Xu S;Hobbie SN;Sha SH;Schacht J;Chow CS;Vasella A;Böttger EC;Crich D
我们描述了一种基于5-O-β-D-呋喃核糖基的安普霉素衍生物（apravine）的收敛合成，该衍生物对野生型ESKAPE病原体的抗菌活性比母体安普霉素显着提高。此外，在存在作用于母体的唯一氨基糖苷修饰酶（AAC（3）-IV）的情况下，新的aprabin保留了优异的抗菌活性，而不会引起对APH（3 '）机制的敏感性，APH（3'）机制通过核糖5-位的磷酸化使其他5-O-β-D-呋喃核糖基2-脱氧链霉胺型氨基糖苷失活。与这种抗菌活性一致，新的aprabyl在无细胞翻译试验中具有优异的30 nM抑制细菌核糖体蛋白质合成的活性（IC 50），同时保留了亲本对细菌核糖体抑制的优异全面选择性。总之，这些特征转化为对E.在小鼠大腿感染模型中，维斯母体相比，小鼠耳蜗外植体中的耳毒性降低。提出了基于亲和素概念的下一代氨基糖苷类抗生素，其在体内和体外显示出优异的活性，对细菌的抑制优于杂合真核核糖体的优异的全面选择性，在离体模型中的最小耳毒性，并且其避开了AAC（3）-IV，AAC（3）-IV是目前唯一作用于母体的氨基糖苷类修饰酶。
We describe the convergent synthesis of a 5-O-β-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3’) mechanism that disables other 5-O-β-D-ribosfuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC50) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in-vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants. A next generation aminoglycoside antibiotic based on the apralog concept is presented that displays excellent activity in vivo and in vitro, excellent across the board selectivity for the inhibition of bacterial over hybrid eukaryotic ribosomes, minimal ototoxicity in an ex-vivo model, and which circumvents AAC(3)-IV, the only current aminoglycoside modifying enzyme acting on the parent.
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影响因子：
15
作者：
Alper, PB;Hendrix, M;Wong, CH
通讯作者：
Wong, CH
影响因子：
30.8
作者：
PREZANT, TR;AGAPIAN, JV;FISCHELGHODSIAN, N
通讯作者：
FISCHELGHODSIAN, N
影响因子：
5.6
作者：
Plattner M;Gysin M;Haldimann K;Becker K;Hobbie SN
通讯作者：
Hobbie SN
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.
影响因子：
4.6
作者：
Ishikawa, Masaaki;Garcia-Mateo, Nadia;Beatriz Duran-Alonso, M.
通讯作者：
Beatriz Duran-Alonso, M.