Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Sci Rep. 2017 Jan 10;7:40077. doi: 10.1038/srep40077.
Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1β. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.
甲萘醌（MK）生物合成途径是评估革兰氏阳性菌中抗菌药物的潜在靶标。在这里，我们以 1,4-二羟基-2-萘醌 prenyltransferase（MenA）为靶点，以减少耐甲氧西林金黄色葡萄球菌（MRSA）的生长。设计、合成并评估了具有抑制 MenA 作用的长链化合物，以评估其对需氧条件下 MRSA 和利用甲萘醌的细菌的作用。结果表明，这些细菌对大多数化合物敏感。甲萘醌（MK-4）的补充挽救了 MRSA 的生长，表明这些化合物抑制了 MK 的生物合成。化合物 3a 和 7c 对 MRSA 菌株的 MIC 范围为 1-8μg/ml，表现出有希望的抑制活性。这些化合物不会促进小菌落变体的形成。这些化合物还能抑制高浓度 MRSA 的生物膜生长。化合物 3a、6b 和 7c 在与各自 MIC 相等和四倍浓度下对 MRSA 显示出有希望的细胞外杀菌活性。我们还观察到用化合物 3a、6b 和 7c 处理 THP-1 巨噬细胞释放的细胞因子，并发现 TNF-α 和 IL-6 的释放减少，IL-1β 的释放增加。这些数据表明，MenA 抑制剂作为 TNF-α 和 IL-6 的抑制剂发挥作用，这为这些化合物作为潜在的免疫调节剂的开发和应用提供了依据。
