Emerging Bacterial Pathogens (Brigitte GICQUEL)
The main research interests
Tuberculosis is an infectious disease that typically attacks the lungs and is essentially caused by the bacteria Mycobacterium tuberculosis. Tuberculosis has been present in humans since antiquity and still a top infectious disease killer worldwide. According to WHO, in 2014, 9.6 million people fell ill with TB and 1.5 million died from the disease.
Although tuberculosis is curable when sensitive to the classical quadri-therapy, antibiotic resistance is a major public health problem. The difficulty to efficiently treat patients with multiple antibiotic resistances pinpoints the need to identify new antibiotics as well as rapid approaches to detect antibiotic resistances. A very limited number of new antibiotics have been discovered during the two last decades and only one new drug against tuberculosis, bedaquiline, was discovered and used for treatment despite his toxicity. Many more molecules should be identified in order to have a chance to develop a portfolio that will be suitable for the treatment of multidrug resistant (MDR) and extremely drug resistant (XDR) tuberculosis and mycobacteriosis due to mycobacteria with intrinsic resistance to most antibiotics.
In order to discover new compounds with anti-mycobacterial activities, we use whole cell screening which involves measuring the growth of bacteria in the presence of potential inhibitors. Until now, the different screenings of chemical libraries were being done with single bacterial species Mycobacterium tuberculosis, M. bovis BCG or M. smegmatis. Given that a very limited number of drug candidates have been discovered, we propose a new approach consisting in using two different mycobacterial species, M. aurum and M. marinum, not previously used to identify molecules with anti-mycobacterial activity. M. smegmatis, M. marinum and M. aurum exhibit different antibiotic resistance profiles. The parallel screening of drugs with such strains will provide valuable information for the search for new active drugs against bacterial pathogens.We use chemical libraries made of synthetic molecules or natural products for the screening. These compounds are from the Chinese National Compound Library and the Fudan University in Shanghai. The screening makes use of robotic platform or semi-automatic system. The minimal inhibitory concentration (MIC) of the identified hit is determined on several mycobacterial species (M. aurum, M. marinum, M. smegmatis, M. abscessus, M. bovis, M. tuberculosis) and compared with the MIC for antibiotics used in clinic. For the optimization of the potency of lead compounds, we are looking for series of compounds with structures similar to these molecules previously identified.
In order to identify drug targets, mutants resistant to the molecules showing anti-mycobacterial activity are isolated and their genomes sequenced. Mutations specifically observed in mutants resistant to a given molecule allow us to identify genes responsible for sensitivity/resistance to this molecule.
The study of the mechanisms of action of these molecules and the mechanisms of natural resistance to these antibiotic candidates will be studied with the aim of improving the antibiotic candidate and proposing an optimal regimen for their utilization in clinic.
? Mycobacterial Genetics Unit, Institut Pasteur of Paris
? QianGao, and Jin-Feng Hu, Shanghai Medical College and pharmacology department,Fudan University.
? The Shanghai CDC
? National Laboratories of Public Health in Gabon
? Partner Institute for Computational Biology, Max Planck Society in Shanghai
The National Center for Drug Screening