Go to content Go to the menu Go to the search

PartnersSorbonne UniversitésUPMCInsermCNRS
Quick access, personalized services
Centre d'Immunologie et des Maladies Infectieuses
UPMC UMRS CR7 - Inserm U1135 - CNRS ERL 8255

Emergence and Diffusion of Multiple Drug Resistance against antibiotics - Wladimir SOUGAKOFF

Team members

Team Research Program

The research activity of our group is aimed at elucidating the mechanisms of emergence and diffusion of multiple drug resistance (MDR) in bacteria,on two models: chromosome-born MDR in Mycobacterium tuberculosis (Mtb) and plasmid-born MDR in Enterobacteriaceae.

Chromosome-born multidrug resistance (MDR) in M.tuberculosis (Mtb)

Our objectives are: (i) To decipher the drug-resistance machinery in Mtb by studying at the genome level the variety of mutations involved in resistance to anti-tuberculous drugs. (ii) to study the links between drug-resistance spreading and phylogenic lineages of Mtb through genomic studies. (iii) to investigate at biochemical and structural levels, two unique M. tuberculosis macromolecular complexes of interest for the development of new drugs, the unique topoisomerase II of M.tuberculosis (DNA gyrase) and the mycobacterial ATP synthase. (iv) to develop new murine models to evaluate the impact of the immune status of the host, particularly the formation of the hypoxic granuloma, on the frequency and diversity of resistant mutants selected in vivo under antiTB therapy, and assess the activity of new drug combinations (e.g. ethionamide-ETH boosters or carbapenem-clavulanate)  for treating MDR tuberculosis.

Molecular mechanisms contributing to the spread of plasmids carrying multiple resistance genes

The aim of this project is to investigate the molecular mechanisms contributing to the spread of plasmids carrying multiple resistance genes in Enterobacteriaceae, with a specific focus on the two major human pathogens: Escherichia coli and Klebsiella pneumoniae.
Our goals are (i) The establishment of a plasmid sequence database to increase our understanding of the origin and evolution of MDR plasmids in these two species. A special focus is on functions involved in the accumulation of resistance genes, on the spreading of multi-resistant plasmids and on the maintenance of such plasmids in the bacterial host. (ii) To evaluate the contribution of multiple replication systems on the diffusion capacity of MDR plasmids showing an unusually extended bacterial host range. (iii) To understand the contribution of partition systems and toxin-antitoxin systems on the maintenance capacity of MDR plasmids.

Technical expertise

  • Microbiology (mycobacteria, Gram+, Gram-)
  • Murine models of tuberculosis
  • Analysis of plasmids (cloning-sequencing)
  • Analysis of antibiotics interacting proteins
  • Epidemiological investigations

Main achievements

  • Crystal structure of the catalytic core of the DNA gyrase of M. tuberculosis
  • Crystal structure of PncA, the pyrazinamidase of M. tuberculosis
  • Development of a new therapeutic scheme including TMC207 reducing duration of tuberculosis treatment from 6 to 4 months.
  • Characterization of genetic backgrounds involved in the mobilization of beta-lactamase genes.
  • First characterization of the globally disseminated clone of E. coli ST131-025B carrying CTX-M-15, and determination of its uropathogenicity and ability to intestinal colonization, in a mouse model

External funding (current)

At academic level:

  • 2014-2015 : PHRC Fast-TB (N. Veziris, 2014-2015)
  • 2014-2015:  DIM Mal Inf (A. Aubry)
  • 2015 : SATT LUTECH MA0077 (A. Aubry)
  • 2013-2014 : ESCMID Research Grant  (A. Renvoisé)
  • 2010-2014 : PHRC CaMoMy (N. Veziris)
  • 2010-2014 : PHRC Ecarb (J. Robert, D. Decré, G. Arlet)
  • 2010-2014 : WHO Clinical Trial on Buruli ulcer treatment (J. Robert)

From industry:

  • 2014 : Janssen Research and Development. Genotyping of M. tuberculosis from patients of TMC207 Clinical Trial (W. Sougakoff)
  • 2014 : Bayer HealthCare - Essai clinique 13805 Inhaled Amikacin Solution as Adjunctive Therapy in the treatment of Gram-Negative Pneumonia (A.Aubry)
  • 2015 : Janssen Infectious Diseases – Diagnostics. Activity of bedaquiline in culture media  (V. Jarlier)

Publications (PDF):

(2017 - 2016- 2015 - 2014 - 2013)

23/10/17

Traductions :

Contact

cimi-paris @ upmc.fr

To see

Key words

Resistance to antibiotics, Tuberculosis, Mycobacteria, Enterobacteria, DNA gyrase, Epidemiology,  Genotyping, Experimental chemotherapy

Fields of application

Bacteriology, Epidemiology of antibiotics resistance, Molecular mechanisms of antibacterial drug resistance, Molecular mechanisms of plasmid maintenance, Analysis of drug targets, New anti-tuberculous treatments