Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold.
Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold.
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DOI：
10.1021/acs.jmedchem.6b00640
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发表时间：
2016-09-08
影响因子：
7.3
通讯作者：
Cai J
中科院分区：
文献类型：
--
作者：
Teng P;Huo D;Nimmagadda A;Wu J;She F;Su M;Lin X;Yan J;Cao A;Xi C;Hu Y;Cai J
耐药细菌的流行已成为21世纪最大的威胁之一。在此，我们报道了一系列基于酰化还原酰胺支架的小分子抗菌剂的开发。这些分子对一组多重耐药革兰氏阳性和革兰氏阴性细菌菌株显示出良好的效力。同时，它们也有效地抑制生物膜的形成。机制研究表明，这些化合物通过破坏细菌膜来杀死细菌，这是一种类似于宿主防御肽（HDPs）的机制。该机制进一步得到以下事实的支持：即使在14代之后，先导化合物也不会诱导MRSA细菌的耐药性。最后，我们还证明了这些分子通过预防大鼠模型中由MRSA诱导的肺炎引起的炎症具有治疗潜力。这类化合物可能会导致一类有吸引力的抗生素药物对抗耐药菌株。
Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). The mechanism is further supported by the fact that the lead compounds do not induce resistance in MRSA bacteria even after 14 passages. Lastly, we also demonstrate that these molecules have therapeutic potential by preventing inflammation caused by MRSA induced pneumonia in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.