Konai Mohini M, Haldar Jayanta
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
ACS Infect Dis. 2015 Oct 9;1(10):469-78. doi: 10.1021/acsinfecdis.5b00056. Epub 2015 Aug 25.
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 β-lactam-resistant Klebsiella pneumoniae. An optimized compound in the series showed activity against planktonic bacteria in the concentration range of 3-10 μg/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.
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，细菌生物膜的形成是另一个令人担忧的原因，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兼具抗菌和抗生物膜活性。在本研究中，我们设计了基于赖氨酸的小分子，其不仅表现出值得称赞的广谱抗菌活性，还具有强大的生物膜破坏特性。这些亲脂性赖氨酸 - 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、粪肠球菌）和革兰氏阴性菌（大肠杆菌）表现出强大的抗菌活性，包括耐药超级细菌耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素粪肠球菌（VRE）和耐β - 内酰胺肺炎克雷伯菌。该系列中的一种优化化合物在3 - 10μg/mL的浓度范围内对浮游细菌具有活性，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）相对于人红细胞还表现出约120倍的选择性。这种快速杀菌化合物主要通过引起显著的膜去极化和K(+)泄漏作用于细菌。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，这类化合物具有很高的潜力被开发为未来的抗菌药物，用于治疗由浮游细菌以及细菌生物膜引起的感染。
