Department of Biology, New Mexico Tech, 801 Leroy Place, Socorro, NM 87801, USA.
Department of Chemistry, New Mexico Tech, 801 Leroy Place, Socorro, NM 87801, USA.
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1879-1886. doi: 10.1016/j.bmcl.2018.04.001. Epub 2018 Apr 3.
Compounds based on the 2,3-distyrylindole scaffold were found to exhibit bactericidal properties upon irradiation with white light. At the concentration of 1 μM, the lead compound 1 completely (ca. 10 CFU/mL) eradicated such Gram-positive organisms as S. aureus (MRSA, MSSA), E. faecalis (VRE), S. pyogenes and S. mutans when irradiated with white light for 2 min. At the concentration of 5 μM and in the presence of polymyxin E at non-bactericidal 1.25 μg/mL concentration, 1 also showed a 7-log to 9-log reductions in bacterial counts of such Gram-negative organisms as multi-drug resistant (MDR) A. baumannii, MDR P. aeruginosa, E. coli and Klebsiella pneumoniae (CRE: KPC and NDM-1), also when irradiated with white light for 2 min. The structure-activity relationship studies revealed that unsubstituted at benzene rings 2,3-distyrylindole 2 was most potent and gave a 5-order of magnitude eradication of a MRSA strain at the concentration of 30 nM upon irradiation with white light. Initial mechanistic experiments revealed the disruption of bacterial cell membrane, but indicated that singlet oxygen production, which is commonly associated with photodynamic therapy, may not play a role in the bactericidal effects of the 2,3-distyrylindoles.
基于 2,3-二取代茚满骨架的化合物在白光照射下表现出杀菌特性。在 1μM 的浓度下，先导化合物 1 在白光照射 2 分钟后完全（约 10 CFU/mL）消除了革兰氏阳性菌，如金黄色葡萄球菌（MRSA、MSSA）、粪肠球菌（VRE）、化脓性链球菌和变异链球菌。在 5μM 的浓度下，当聚维酮 E 以非杀菌浓度 1.25μg/mL 存在时，化合物 1 也能使多药耐药（MDR）鲍曼不动杆菌、MDR 铜绿假单胞菌、大肠杆菌和肺炎克雷伯菌（CRE：KPC 和 NDM-1）的细菌计数减少 7 到 9 个对数级，同样在白光照射 2 分钟后。构效关系研究表明，苯环上未取代的 2,3-二取代茚满 2 是最有效的，在白光照射下，浓度为 30nM 时就能消灭一株 MRSA 菌株，达到 5 个数量级。初步的机制实验表明，细菌细胞膜被破坏，但表明与光动力疗法相关的单线态氧的产生可能在 2,3-二取代茚满的杀菌作用中不起作用。
