Identification of a small molecule that simultaneously suppresses virulence and antibiotic resistance of Pseudomonas aeruginosa

Qiaoyun Guo, Yu Wei, Bin Xia, Yongxin Jin, Chang Liu, Xiaolei Pan, Jing Shi, Feng Zhu, Jinlong Li, Lei Qian, Xinqi Liu, Zhihui Cheng, Shouguang Jin, Jianping Lin, Weihui Wu

Scientific RepoRts | 6:19141 | DOI: 10.1038/srep19141

Speaker: Pei-Chun Li (李姵君)                                            Time: 13:00~14:00, Apr. 6, 2016

Commentator: Jenn-Wei Chen, Ph.D (陳振暐 老師)          Place: Room 601

Abstract:

        The antibiotic resistance of bacteria imposes a severe threat on human health, while the pipeline of new antibiotics development is running dry. Molecules targeting bacterial virulence can disarm pathogens in the hosts, allowing host immune system and normal flora to prevent or eradicate the infection.[1] The authors combined genetic and computer-aided inhibitor screening to search for such molecules against the bacterial pathogen Pseudomonas aeruginosa. P. aeruginosa directly injects bacterial effector molecules into host cell cytosol through a type III secretion system (T3SS), causing disruption of intracellular signaling or cell death. During infection, P. aeruginosa secrets siderophores to acquire iron from host, which is essential for the bacterial growth. The quorum sensing (QS) system regulates the expression of multiple virulence factors and plays important roles in the P. aeruginosa pathogenesis. To identified P. aeruginosa genes that are required for both antibiotic resistance and pathogenesis, the authors utilizing the nonredundant library of PA14 transposon mutants, the authors found that PyrD is required for multiple virulence factors, such as T3SS, quorum sensing, iron acquisition, biofilm formation as well as antibiotic resistance. Therefore, they chose PyrD as the chemotherapeutic target for further experimentations. Next, the authors screen for small molecules targeting P. aeruginosa DHODase. They determinated the P. aeruginosaDHODase and concentration-dependent inhibition of recombinant P. aeruginosa DHODase by the compound 14. Compound 14 modestly reduced the expression of T3SS genes and bacterial cytotoxicity. Therefore, molecules targeting the pyrimidine synthetic pathway might be promising antimicrobials.

References:

1. Duncan, M. C., Linington, R. G. & Auerbuch, V. Chemical inhibitors of the type three secretion system: disarming bacterial pathogens. Antimicrob Agents Chemother 56, 5433–5441 (2012).