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

1,†, 2,†, 2, 2,* and 1,*
1
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong
2
Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(16), 2902; https://doi.org/10.3390/molecules24162902
Received: 15 July 2019 / Revised: 7 August 2019 / Accepted: 8 August 2019 / Published: 9 August 2019
(This article belongs to the Section Bioorganic Chemistry)
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Abstract

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. View Full-Text
Keywords: RNA polymerase; sigma factor; transcription; inhibitor; antimicrobial discovery RNA polymerase; sigma factor; transcription; inhibitor; antimicrobial discovery
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Ye, J.; Chu, A.J.; Lin, L.; Yang, X.; Ma, C. 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 2019, 24, 2902.

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