Lysine-Based Small Molecules That Disrupt Biofilms and Kill both Actively Growing Planktonic and Nondividing Stationary Phase Bacteria
Lysine-Based Small Molecules That Disrupt Biofilms and Kill both Actively Growing Planktonic and Nondividing Stationary Phase Bacteria
复制标题
DOI：
10.1021/acsinfecdis.5b00056
复制
发表时间：
2015-10-01
影响因子：
5.3
通讯作者：
Haldar, Jayanta
中科院分区：
文献类型：
--
作者：
Konai, Mohini M.;Haldar, Jayanta
细菌耐药性的出现是对全球健康的重大威胁。除了这个问题之外，细菌生物膜的形成也是令人担忧的另一个原因，因为大多数抗生素对这些顽固的微生物群落无效。理想的未来抗菌疗法应同时具有抗菌和抗生物膜活性。在这项研究中，我们设计了基于赖氨酸的小分子，它不仅表现出值得称赞的广谱抗菌活性，而且还具有有效的生物膜破坏特性。这些亲脂性赖氨酸-去甲亚精胺缀合物的合成通过三个简单的反应步骤实现，所得分子对各种革兰氏阳性菌（金黄色葡萄球菌、屎肠球菌）和革兰氏阴性菌（大肠杆菌）显示出有效的抗菌活性，包括耐药超级细菌MRSA（耐甲氧西林金黄色葡萄球菌）、VRE（耐万古霉素大肠杆菌）。屎肠球菌）和耐β-内酰胺肺炎克雷伯菌。该系列中的优化化合物在3-10μg/mL的浓度范围内表现出对浮游细菌的活性，并且在一小时内观察到对静止期金黄色葡萄球菌的杀菌活性。该化合物对两类细菌（金黄色葡萄球菌和大肠杆菌）的选择性比人类红细胞高约 120 倍。这种快速杀菌化合物主要通过引起显着的膜去极化和 K+ 泄漏来作用于细菌。最重要的是，该化合物破坏了金黄色葡萄球菌预先形成的生物膜，并且不会引发细菌耐药性。因此，此类化合物具有很大的潜力被开发为未来用于治疗浮游细菌和细菌生物膜引起的感染的抗菌药物。
The emergence of bacterial resistance is a major threat to global health. Alongside this issue, formation of bacterial biofilms is another cause of concern because most antibiotics are ineffective against these recalcitrant microbial communities. Ideal future antibacterial therapeutics should possess both antibacterial and anti-biofilm activities. In this study we engineered lysine-based small molecules, which showed not only commendable broad-spectrum antibacterial activity but also potent biofilm-disrupting properties. Synthesis of these lipophilic lysine-norspermidine conjugates was achieved in three simple reaction steps, and the resultant molecules displayed potent antibacterial activity against various Gram-positive (Staphylococcus aureus, Enterococcus faecium) and Gram-negative bacteria (Escherichia coli) including drug-resistant superbugs MRSA (methicillin-resistant S. aureus), VRE (vancomycin-resistant E. faecium), and beta-lactam-resistant Klebsiella pneumoniae. An optimized compound in the series showed activity against planktonic bacteria in the concentration range of 3-10 mu g/mL, and bactericidal activity against stationary phase S. aureus was observed within an hour. The compound also displayed about 120 fold selectivity toward both classes of bacteria (S. aureus and E coli) over human erythrocytes. This rapidly bactericidal compound primarily acts on bacteria by causing significant membrane depolarization and K+ leakage. Most importantly, the compound disrupted preformed biofilms of S. aureus and did not trigger bacterial resistance. Therefore, this class of compounds has high potential to be developed as future antibacterial drugs for treating infections caused by planktonic bacteria as well as bacterial biofilms.