College of Veterinary Medicine, Sichuan Agriculture University, Chengdu 610000, China.
Toxins (Basel). 2018 Sep 23;10(10):385. doi: 10.3390/toxins10100385.
With continuous emergence and widespread of multidrug-resistant infections, common antibiotics have become ineffective in treating these infections in the clinical setting. Anti-virulence strategies could be novel, effective therapeutic strategies against drug-resistant bacterial infections. Sortase A (srtA), a transpeptidase in gram-positive bacteria, can anchor surface proteins that play a vital role in pathogenesis of these bacteria. SrtA is known as a potential antivirulent drug target to treat bacterial infections. In this study, we found that erianin, a natural bibenzyl compound, could inhibit the activity of srtA in vitro (half maximal inhibitory concentration-IC = 20.91 ± 2.31 μg/mL, 65.7 ± 7.2 μM) at subminimum inhibitory concentrations (minimum inhibitory concentrations-MIC = 512 μg/mL against ). The molecular mechanism underlying the inhibition of srtA by erianin was identified using molecular dynamics simulation: erianin binds to srtA residues Ile182, Val193, Trp194, Arg197, and Ile199, forming a stable bond via hydrophobic interactions. In addition, the activities of binding to fibronectin and biofilm formation were inhibited by erianin, when co-culture with . In vivo, erianin could improve the survival in mice that infected with by tail vein injection. Experimental results showed that erianin is a potential novel therapeutic compound against infections via affecting srtA.
随着多药耐药感染的不断出现和广泛传播，临床上常用的抗生素已无法有效治疗这些感染。抗毒力策略可能是治疗耐药细菌感染的新型有效治疗策略。葡萄球菌中的转肽酶 Sortase A（srtA）可以固定在表面的蛋白，这些蛋白在这些细菌的发病机制中起着至关重要的作用。srtA 被认为是治疗细菌感染的潜在抗毒力药物靶点。在本研究中，我们发现，白杨素，一种天然的联苯化合物，可在亚最小抑菌浓度（最低抑菌浓度-MIC = 512 μg/mL 时）下体外抑制 srtA 的活性（半最大抑制浓度-IC = 20.91 ± 2.31 μg/mL，65.7 ± 7.2 μM）。使用分子动力学模拟确定了白杨素抑制 srtA 的分子机制：白杨素结合 srtA 的残基 Ile182、Val193、Trp194、Arg197 和 Ile199，通过疏水相互作用形成稳定的键。此外，当与 共培养时，白杨素抑制了 与纤维连接蛋白的结合和生物膜的形成。在体内，尾静脉注射白杨素可以提高感染 的小鼠的存活率。实验结果表明，白杨素通过影响 srtA 成为一种治疗 感染的新型潜在治疗化合物。
