Evaluation of small molecule SecA inhibitors against methicillin-resistant Staphylococcus aureus.
Evaluation of small molecule SecA inhibitors against methicillin-resistant Staphylococcus aureus.
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DOI：
10.1016/j.bmc.2015.09.027
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发表时间：
2015-11-01
影响因子：
3.5
通讯作者：
Tai PC
中科院分区：
文献类型：
--
作者：
Jin J;Cui J;Chaudhary AS;Hsieh YH;Damera K;Zhang H;Yang H;Wang B;Tai PC
由于细菌耐药性的出现和迅速传播，迫切需要开发新型抗菌药。SECA是生存和毒力所需的一般细菌分泌系统的关键组成部分，是一个有吸引力的抗菌素靶标。早些时候，我们报道了对SECA抑制剂Rose Bengal(RB)的系统剖析，导致了对大肠杆菌和枯草杆菌具有活性的新型小分子SECA抑制剂的开发。在这项研究中，进一步评估了两个有效的Rb类似物对耐甲氧西林金黄色葡萄球菌(MRSA)菌株的活性及其作用机制。这些类似物对金黄色葡萄球菌SecA1(SaSecA1)和SecA2(SaSecA2)的ATPase活性有抑制作用，对依赖SaSecA1的蛋白传导通道也有抑制作用。此外，这些抑制剂减少了金黄色葡萄球菌三种毒素的分泌，并对三种MRSA菌株具有很强的抑菌作用。我们最好的抑制剂SCA-50对MRSA Mu50菌株显示出强大的浓度依赖杀菌活性，非常重要的是，对MRSA Mu50的抑制作用是包括万古霉素在内的所有常用抗生素的2-60倍，万古霉素被认为是治疗MRSA相关感染的最后选择。蛋白质下拉实验进一步证实了SaSecA1是一个目标。NorA和MEPA外排泵的缺失或过表达对金黄色葡萄球菌的抗菌活性影响很小，表明SECA抑制剂的作用不受这两个外排泵的影响。我们的研究表明，这些小分子类似物以SecA功能为靶点，具有强大的抗菌活性，减少毒素的分泌，并有能力克服导致多药耐药的外排泵效应。因此，靶向SecA是对抗MRSA的一种有吸引力的抗菌策略。
Due to the emergence and rapid spread of drug resistance in bacteria, there is an urgent need for the development of novel antimicrobials. SecA, a key component of the general bacterial secretion system required for viability and virulence, is an attractive antimicrobial target. Earlier we reported that systematical dissection of a SecA inhibitor, Rose Bengal (RB), led to the development of novel small molecule SecA inhibitors active against E. coli and B. subtilis. In this study, two potent RB analogs were further evaluated for activities against methicillin-resistant Staphylococcus aureus (MRSA) strains and for their mechanism of actions. These analogs showed inhibition on the ATPase activities of S. aureus SecA1 (SaSecA1) and SecA2 (SaSecA2), and inhibition of SaSecA1-dependent protein-conducting channel. Moreover, these inhibitors reduce the secretion of three toxins from S. aureus and exert potent bacteriostatic effects against three MRSA strains. Our best inhibitor SCA-50 showed potent concentration-dependent bactericidal activity against MRSA Mu50 strain and very importantly, 2–60 fold more potent inhibitory effect on MRSA Mu50 than all the commonly used antibiotics including vancomycin, which is considered the last resort option in treating MRSA-related infections. Protein pull down experiments further confirmed SaSecA1 as a target. Deletion or overexpression of NorA and MepA efflux pumps had minimal effect on the antimicrobial activities against S. aureus, indicating that the effects of SecA inhibitors were not affected by the presence of these efflux pumps. Our studies show that these small molecule analogs target SecA functions, have potent antimicrobial activities, reduce the secretion of toxins, and have the ability to overcome the effect efflux pumps, which are responsible for multi-drug resistance. Thus, targeting SecA is an attractive antimicrobial strategy against MRSA.