Chojnacki Michaelle, Cao Xufeng, Flaherty Daniel P, Dunman Paul M
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University 575 Stadium Mall Dr., West Lafayette, IN 47907, USA.
Antibiotics (Basel). 2021 Mar 31;10(4):369. doi: 10.3390/antibiotics10040369.
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 disease. To that end, 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 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.
众所周知，由于抗生素耐药性的出现，它会导致难以治疗的使人衰弱的细菌感染。因此，需要开发新的抗菌药物用于疾病的治疗干预。为此，RnpA是一种必需的酶，据推测它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确定苯基氨基甲酰基环噻吩类作为RnpA抑制剂的化学类别，其通过降低RnpA的ptRNA和mRNA降解活性以及低人细胞毒性而显示出有前景的抗菌作用。在此，我们对该化学支架进行了构效关系研究。结果表明，环烷烃环大小和三氟乙酰胺部分对抗菌活性是必需的，而药效基团苯基的对位和/或间位修饰允许调节支架的抗菌性能和RnpA抑制活性。在抗菌活性方面表现最佳的化合物在浓度高达100 μM时对人细胞系也未表现出细胞毒性，该浓度比最低抑菌浓度（MIC）高100倍以上。对一种类似物RNP0012进行的重点研究显示，该化合物在疾病的小鼠模型中降低了细菌载量，RNP0012表现出最有效的抗菌作用并抑制细胞RnpA活性。综上所述，所呈现的结果有望为优化下一代RnpA抑制剂类似物提供早期框架，这些类似物可能代表一类新型抗菌药物的前身。
