First-In-Class Inhibitors Targeting the Interaction between Bacterial RNA Polymerase and Sigma Initiation Factor Affect the Viability and Toxin Release of Streptococcus pneumoniae

Molecules

AdrianJun Chu¹  Lin Lin¹  Xiao Yang¹  Jiqing Ye²  Cong Ma² 

[1] Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong;State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong;

关键词: RNA polymerase;    sigma factor;    transcription;    inhibitor;    antimicrobial discovery;   

DOI  :  10.3390/molecules24162902

来源: DOAJ

【 摘 要 】

Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound (C3) was previously identified from a pharmacophore model-based in silico screen. In this study, the hit compound was experimentally assessed with some rationally designed derivatives for the antimicrobial activities, in particular against Streptococcus pneumoniae and other pathogens. One compound, C3-005, shows dramatically improved activity against pneumococci compared to C3. C3-005 also attenuates S. pneumoniae toxin production more strongly than existing classes of antibiotics tested. Here we demonstrate a newly validated antimicrobial agent to address an overlooked target in the hit-to-lead process, which may pave the way for further antimicrobial development.

【 授权许可】

Unknown