北海道大学 大学院理学研究院 化学部門

生物化学研究室

講演者

Prof. Christian Baron
（Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal）

日時

平成27年3月24日（火）　10:35-11：20

場所

北海道大学理学部　6号館　2階04-2室＜多目的演習室＞

概要

The resistance to antimicrobial drugs keeps increasing and we therefore need to develop alternative strategies to treat infectious diseases. The classical approach for the design of antibiotics is to target essential metabolic functions in order to either kill bacteria or stop their growth. This strategy was very successful in the past, but the strong selection pressure by antibiotics has contributed to the increasing occurrence of multi-resistant bacteria. The goal of our work is to develop a novel alternative to antibiotics: Anti-virulence (anti-infective) drugs that target bacterial virulence factors. These molecules will disarm pathogens so that they can be eliminated by the immune system. Since such drugs would not target essential metabolic processes, the selection for resistance will be reduced as compared to classical antibiotics. Anti-virulence drugs alone, or given as combination therapy with antibiotics, would constitute a major advancement for the treatment of infectious diseases.

We are pursuing this approach using bacterial type IV secretion systems as targets. These systems are essential for the virulence of many bacterial pathogens such as Brucella species, Bordetella pertussis, Helicobacter pylori and Legionella pneumoniae, and they are likely required for the virulence of Coxiella and Rickettsia species. The specific targets of our work are VirB8 from the select agent Brucella, and CagV and CagL from H. pylori, type IV secretion proteins that are essential for bacterial virulence. High-throughput screening using a bacterial two hybrid system-based in vivo system identified specific small-molecule inhibitors of VirB8. One of these molecules was a potent inhibitor of the intracellular replication of Brucella in a macrophage infection model. The binding site of inhibitors on VirB8 was identified by X-crystallography, docking and by structure-function analysis of the binding site. A first round of structure-activity relationship analysis defined key features of active inhibitors, and we have further improved these molecules by medicinal chemistry.

We are also conducting structure- and fragment-based screening approaches to identify inhibitors of H. pylori proteins CagV and CagL. Ultimate goal of this work is to find inhibitors of the virulence of this important human pathogen that is present in the gastric mucosa of about 50% of the world’s population. H. pylori causes persistent inflammation and conditions such as gastric or duodenal ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. For this reason, H. pylori was classified as a Class 1 carcinogen by the World Health Organization (WHO). Drug resistance is increasing in this organism and new treatment strategies are therefore urgently needed.

主催

Ambitious物質科学セミナー

共催

生命分子化学セミナー

連絡先

北海道大学 大学院理学研究院 化学部門
生物化学研究室
坂口 和靖
TEL: 011-706-2698