Several mycobacterial species have been used for the screening of chemical libraries with the aim of avoiding natural resistance mechanisms developed by specific species. In this way, different compounds with antibacterial activity have been identified. Mutants resistant to each compound have been isolated and their genomes have been sequenced. The comparison of these sequences with the wild type strain genome will allow us to identify the targets for the antibacterial activity and the mechanism of action of the molecules. This will be instrumental for improving molecules for a better antibacterial activity with emphasis on tuberculosis.

Horizontal gene transfer (HGT) is a major driving force of bacterial diversification. For mycobacteria, a special type of HGT was described in Mycobacterium smegmatis which is linked to distributive conjugal transfer (Gray et al., PLoS Biology, 2013). In the current project we are trying to reproduce the results and explore the process.

Human macrophages are the main cell target of Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. Once phagocytosed, bacilli escape bactericidal functions of macrophages and they multiply inside the cell. Understanding interactions between bacilli and human phagocytes is primordial to develop new strategies to combat tuberculosis. We propose a project aiming at deciphering cell-cell communications between infected cells and non-infected cells. We will use the transcriptomic and the proteomic approaches to discriminate the global response of these differents sub-populations. To our knowledge, this work represents the first study that combines two different levels for the identification of a specific response of infected-cells and neighboring non-infected cells. This study would determine cellular markers of a Mtb signature.

Mycobacterium tuberculosis is an extremely successful, aerosol-transmitted human pathogen, thought to have evolved from a Mycobacterium canettii-like progenitor. In contrast, extant M. canettii strains are rare, genetically diverse and geographically restricted mycobacteria of only marginal epidemiological importance. Comparative genome studies of several Mycobacterium canettii strains previously identified genetic events that contribute to the contrasting evolutionary success observed between M. canettii and M. tuberculosis strains. In this project we now focus on the genetic factors required for the emergence of highly specialised, virulent tuberculosis bacilli.

Label free quantification of proteins after the infection with M. tuberculosis. Macrophages isolated from seven patients were used in this study. Four conditions were compared.

Tuberculosis (TB) still remains a major public health problem with estimated 9 million incident cases and 1.5 million deaths in 2014 (WHO, Global Tuberculosis Report 2015). More worrisome is the emergence of multi drug resistance (MDR), or even extensively resistant (XDR) M. tuberculosis strains worldwide. The standardized treatment of pan-susceptible tuberculosis is the administration of two antibiotics (rifampicin and isoniazid) for six months, accompanied by two additional antibiotics (pyrazinamid and ethambutol) for the first two months. Although very efficacious, this treatment is very demanding due to the duration and the possible side effects. The treatment of MDR-TB is less standardized, with more toxic and poorly tolerated drugs, resulting in lower cure rates. Therefore, we need not only more molecules with antimycobacterial activity, but also, we urgently need new strategies to increase our therapeutic arsenal for treating MDR-TB. Only three new drugs, bedaquiline, delamanid and PA-824 have been tested in phase2/3 clinical trials.

In this context, the european funded project NAREB has been created. It brings together 14 partners from 8 EU Member and Associated States, and it aims to (i) screen different combinations of antibiotic drugs with nano-carriers (lipid, polymeric, biopolymeric) with and without targeting ligands, (ii) coload antibiotics in order to develop innovative therapeutic combination therapies (iii) test in vitro and in vivo the best therapeutic combinations. In particular, we will analyze more in-depth the effect of bedaquilin, new TB drugs and nano-carriers on the host/bacterial transcriptome using RNAseq.

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (MTB), is the deadliest disease due to a single infectious agent. Despite considerable efforts to fight the disease, TB remains a major public health problem. Even more worrying for the future, multidrug resistant (MDR) strains of MTB are continually emerging and about 10% of people with MDR-TB have extensively drug-resistant TB (XDR-TB). Drug-sensitive TB can be cured by a 6-month treatment using 4 antibiotics, but MDR-TB and extensively drug-resistant XDR-TB require treatment for up to 2 years with more toxic and costly second- and third-line drugs. Toxicity of these drugs is well described; it includes hepatotoxicity, liver injury, skin reactions, gastrointestinal and neurological disorders. However how MTB drugs influence the host response to MTB infection has been poorly addressed. The main goal of project is to understand how drugs interact with the host in order to improve the treatment.

We want to automatize the merging of CSV document for data analysis purposes. We've already discussed it with Gael Millot.

The CRBIP, Centre de Ressources Biologiques de l’Institut Pasteur, is a structure created in 2001 that encompasses the Pasteurian culture collections: the CIP (bacteria collection), the PCC (cyanobact

Nous souhaitons analyser les séquences de sept mutant de Mycobacterium marinum générées par l’utilisation de concentrations croissante d’un antibiotique candidat dont nous ne connaissons pas la cible.