Optimization of 2-Acylaminocycloalkylthiophene Derivatives for Activity against Staphylococcus aureus RnpA.
Optimization of 2-Acylaminocycloalkylthiophene Derivatives for Activity against Staphylococcus aureus RnpA.
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DOI：
10.3390/antibiotics10040369
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发表时间：
2021-03-31
期刊：
影响因子：
--
通讯作者：
Dunman PM
中科院分区：
文献类型：
--
作者：
Chojnacki M;Cao X;Flaherty DP;Dunman PM
金黄色葡萄球菌是公认的导致衰弱的细菌感染，由于抗生素耐药性的出现而难以治疗。因此，需要开发新的抗微生物剂用于S.金黄色葡萄球菌病为此，S。金黄色葡萄球菌RnpA是一种必需的酶，假设其参与两个必需的细胞过程，前体tRNA（ptRNA）成熟和mRNA降解。相应的高通量筛选活动已经将苯基氨基甲酰基环噻吩鉴定为一类化学RnpA抑制剂，其通过降低RnpA ptRNA和mRNA降解活性以及低的人类细胞毒性而显示出有希望的抗菌作用。在此，我们进行了化学支架的构效关系研究。结果表明，环烷烃环的大小和三氟乙酰胺部分是所需的抗菌活性，而药效团的苯基基团的帕拉和/或Meta位的修改允许调整的支架的抗微生物性能和RnpA抑制活性。在抗微生物活性方面表现最好的化合物在浓度高达100 µM（大于最小抑制浓度（MIC）的100倍）时也未表现出对人细胞系的细胞毒性。对一种类似物RNP 0012的集中研究显示，该化合物在S.金黄色葡萄球菌病总之，所呈现的结果预计将为优化下一代RnpA抑制剂类似物提供早期框架，这些RnpA抑制剂类似物可能代表一类新的抗菌剂的祖细胞。
Staphylococcus aureus is well-recognized to cause debilitating bacterial infections that are difficult to treat due to the emergence of antibiotic resistance. As such, there is a need to develop new antimicrobials for the therapeutic intervention of S. aureus disease. To that end, S. aureus RnpA is an essential enzyme that is hypothesized to participate in two required cellular processes, precursor tRNA (ptRNA) maturation and mRNA degradation. Corresponding high throughput screening campaigns have identified the phenylcarbamoyl cyclic thiopenes as a chemical class of RnpA inhibitors that display promising antibacterial effects by reducing RnpA ptRNA and mRNA degradation activities and low human cell toxicity. Herein, we perform a structure activity relationship study of the chemical scaffold. Results revealed that the cycloalkane ring size and trifluoroacetamide moiety are required for antibacterial activity, whereas modifications of the para and/or meta positions of the pharmacophore’s phenyl group allowed tuning of the scaffold’s antimicrobial performance and RnpA inhibitory activity. The top performing compounds with respect to antimicrobial activity also did not exhibit cytotoxicity to human cell lines at concentrations up to 100 µM, greater than 100-fold the minimum inhibitory concentration (MIC). Focused studies of one analog, RNP0012, which exhibited the most potent antimicrobial and inhibition of cellular RnpA activities revealed that the compound reduced bacterial burden in a murine model of S. aureus disease. Taken together, the results presented are expected to provide an early framework for optimization of next-generation of RnpA inhibitor analogues that may represent progenitors of a new class of antimicrobials.
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影响因子：
2.1
作者：
Mitchell, DH;Howden, BP
通讯作者：
Howden, BP
DOI：
10.1093/cid/ciy543
发表时间：
2019-01-18
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Bonell A;Azarrafiy R;Huong VTL;Viet TL;Phu VD;Dat VQ;Wertheim H;van Doorn HR;Lewycka S;Nadjm B
通讯作者：
Nadjm B
影响因子：
4.9
作者：
Diekema, Daniel J.;Hsueh, Po-Ren;Jones, Ronald N.
通讯作者：
Jones, Ronald N.
影响因子：
4.9
作者：
Chojnacki, Michaelle;Philbrick, Alesa;Wozniak, Rachel A. F.
通讯作者：
Wozniak, Rachel A. F.
影响因子：
4.9
作者：
Eidem, Tess M.;Lounsbury, Nicole;Dunman, Paul M.
通讯作者：
Dunman, Paul M.