Choi Hyunsuk, Ham So-Young, Cha Eunji, Shin Yujin, Kim Han-Shin, Bang Jeong Kyu, Son Sang-Hyun, Park Hee-Deung, Byun Youngjoo
College of Pharmacy, Korea University , 2511 Sejong-ro, Jochiwon-eup, Sejong 30019, Republic of Korea.
School of Civil, Environmental and Architectural Engineering, Korea University , 145 Anam-ro, Seongbuk-Gu, Seoul 02841, Republic of Korea.
J Med Chem. 2017 Dec 14;60(23):9821-9837. doi: 10.1021/acs.jmedchem.7b01426. Epub 2017 Nov 27.
Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.
铜绿假单胞菌是免疫功能低下患者慢性感染的病原体。破坏群体感应回路是治疗与铜绿假单胞菌感染相关疾病的一种有吸引力的策略。在本研究中，我们设计并合成了一系列靶向LasR的姜辣素类似物，LasR是铜绿假单胞菌群体感应网络的主要调节因子。构效关系研究表明，头部的氢键相互作用、中间部分的立体化学和旋转刚性以及尾部的最佳烷基链长度是增强LasR结合亲和力和抑制生物膜形成的重要因素。最有效的化合物41，一种具有受限旋转的(R)-8-姜辣素类似物，比已知的LasR拮抗剂(S)-6-姜辣素表现出更强的LasR结合亲和力和生物膜形成抑制作用。这种新型LasR拮抗剂可作为开发抗生物膜药物以治疗铜绿假单胞菌感染的早期先导化合物。
