The Path to New Halogenated Quinolines With Enhanced Activities Against Staphylococcus epidermidis.
The Path to New Halogenated Quinolines With Enhanced Activities Against Staphylococcus epidermidis.
复制标题
DOI：
10.1177/1178636118808532
复制
发表时间：
2018-01-01
影响因子：
--
通讯作者：
Huigens, Robert W 3rd
中科院分区：
文献类型：
--
作者：
Huigens, Robert W 3rd
耐药细菌和表面附着的细菌生物膜在人类疾病中起着重要作用。传统抗生素的目标是积极复制的自由漂浮的浮游细胞。不幸的是，生物膜群落被赋予了对抗生素耐受的非复制持久性细胞。需要创新的方法来识别能够根除耐药和耐受细菌细胞的新分子。我们的团队已经发现，选择卤化喹啉（hq）可以根除耐药，革兰氏阳性细菌病原体及其相应的生物膜。有趣的是，HQ支架是合成可调的，我们已经通过广泛的类似物合成和微生物学研究发现了独特的抗菌谱。我们最近报道了14个新的HQs的合成，以研究ClogP值对抗菌和生物膜根除活性的影响。我们对HQ支架的2位进行了不同的合成修饰，试图提高水溶性，并发现了新的化合物，显示出增强的抗表皮葡萄球菌活性。特别是，与耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌分离物相比，HQ 2 （ClogP=3.44）对耐甲氧西林表皮S (MRSE) 35984浮游细胞（最小抑制浓度=0.59M）表现出更强的抗菌活性，同时表现出强的MRSE生物膜根除活性（最小生物膜根除浓度=2.35M）。我们相信HQ可以在下一代抗菌药物的开发中发挥关键作用。
Antibiotic-resistant bacteria and surface-attached bacterial biofilms play a significant role in human disease. Conventional antibiotics target actively replicating free-floating, planktonic cells. Unfortunately, biofilm communities are endowed with nonreplicating persister cells that are tolerant to antibiotics. Innovative approaches are necessary to identify new molecules able to eradicate resistant and tolerant bacterial cells. Our group has discovered that select halogenated quinolines (HQs) can eradicate drug-resistant, gram-positive bacterial pathogens and their corresponding biofilms. Interestingly, the HQ scaffold is synthetically tunable and we have discovered unique antibacterial profiles through extensive analogue synthesis and microbiologic studies. We recently reported the synthesis of 14 new HQs to investigate the impact of ClogP values on antibacterial and biofilm eradication activities. We conducted diverse synthetic modifications at the 2-position of the HQ scaffold in an attempt to enhance water solubility and found new compounds that display enhanced activities against Staphylococcus epidermidis. In particular, HQ 2 (ClogP=3.44) demonstrated more potent antibacterial activities against methicillin-resistant S epidermidis (MRSE) 35984 planktonic cells (minimum inhibitory concentration=0.59M) compared with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus isolates while demonstrating potent MRSE biofilm eradication activities (minimum biofilm eradication concentration=2.35M). We believe that HQ could play a critical role in the development of next-generation antibacterial therapeutics.