Speaker Details

Biography

Address UMR-MD1, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille cedex 05, France. jean-marie.pages@univ-amu.fr Education/Academic degrees PhD Microbiology Biochemistry 1975. Doctorat Es-Sciences 1983 University de la Méditerranée, Marseille, France Position • 2009, Senior Director of Research (DR1) INSERM • 2012, Director of UMR-MD1 Research Unit “Membrane Transporters, Chemoresistance and Drug design” (University-Ministry of Defense). Scientific Committee and Memberships • Member of Scientific Committee on Emerging and Newly Identified Health Risks, EC-DG SANCO • Expert for NSF-USA and NIH-USA, Natural Sciences and Engineering Research Council, Canada, Singapour-National Medical Research Council, 7th PCRDT EC • Member of the Scientific Committee Synchrotron Soleil, Gif/Yvette, France • Member of the Scientific Committee Instituto de Higiene e Medicina Tropical, Lisboa, Portugal European research network • Chair of COST Action BM0701 “ Antibiotic transport and efflux: New strategies to combat bacterial resistance “• European IMI-ND4BB “ Molecular basis of the bacterial cell wall permeability “ 2013-2018. • European ITN-Marie Curie, “ Translocation “ 2013-2017. Science Societies • American Society for Microbiology and Société Française de Microbiologie • Referee for: Nature Med., J. Mol. Biol., Antimicrob. Agents Chemother., etc Honors • Astra/Zeneca/ESMID Wall of resistance Research Grant 2002 “An Analysis of In Vivo Activity of Efflux Pump Inhibitors in Antibiotic-Resistant Enterobacter Aerogenes” • Eloi Collery Prix, National Academy of Medicine, France 2005, “Bacterial membrane and antibiotic resistance mechanisms • Honor Medal of Health Dept. of French Army, 2010 Research Interest • Bacterial membrane transporters, drug efflux pumps (genetic, structural and functional aspects, structural-activity relationship) • Antibiotic resistance mechanisms in bacteria, mechanism-biochemistry, regulation and expression, activity and clinical involvement • New antimicrobial compounds, new target bypassing resistance mechanism Publications and Conferences over 300 scientific publications, abstracts, patents, lectures and communications in bacteriology-biochemistry-chemistry field Some publications: •Pagès et al. The porin and the permeating molecule: a selective diffusion barrier in Gram-negative bacteria. Nature Reviews Microbiology 2008, 6: 893-903. •Tran et al. Functional approach of porin channel: Antibiotic pathway through Providencia porins. J. Biol. Chem. 2010, 285: 32273-81. •Nikaido and Pagès. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol. Rev. 2012, 36:340-363. •Kaščáková et al. Antibiotic Transport in Resistant Bacteria: Synchrotron UV Fluorescence Microscopy to Determine Antibiotic Accumulation with Single Cell Resolution. PloS ONE 2012, 7(6): e38624. • Cinquin et al. Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level. Sci. Reports, 2015, 5, 17968. Lectures (Invitation) • Pagès J.M. Bacterial transporters: the Pandora box of antibiotic resistance. 462nd WE Heraeus Seminar and BM0701 5th MCM-WG meeting, Bremen, Germany, 2010. • Pagès J.M. Modulation of membrane permeability: an efficient response to stress. 21st ECCMID-ICC, Milan, Italy, 2011. • Pagès J.M. Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative organisms. AstraZeneca Infection IMED Annual Infection Symposium. Waltham, Boston, US, 2011. •Pagès J.M. Clinical and in vitro data regarding drug influx - efflux pump occurrence in Gram-negative bacteria, Gordon Research Conferences Multi-Drug Efflux Systems, Ventura, USA 2013. •Pagès J.M. Influx versus Efflux, the accumumation paradigm in Gram negative bacteria: an endless story. ITN-IMI Summer Conferences, Jacobs University, Bremen, Germany, 2015.

Abstract

Challenging antibiotic resistance: antibiotic translocation through bacterial membrane

With the continuing emergence of bacterial multidrug resistance, an important challenge is to better understand membrane translocation of antibiotics through the bacterial envelope. A molecular and genetic dissection of the membrane transport associated with cellular imaging analysis is needed to understand the uptake and the activity of antimicrobial agents in bacterial cells. This is particularly acute for Gram-negative bacteria that contain a sophisticated envelope comprising two membranes, the outer and inner membranes. These membrane barriers efficiently control the transport and the intracellular accumulation of antibiotics by modulating the expression of porins and efflux pumps. The early steps of permeation process were studied within bacterial populations and at a single bacteria level to determine the antibiotic concentration/location in multi-drug resistant isolates and derivative strains. The antibacterial activities were determined in parallel on the same bacterial strains in order to correlate the intracellular accumulation of antibiotic to the bacterial susceptibility. With this original methodology that combines UV fluorescence microscopy, clinically used antibiotics or original molecules, clinical isolates and derivative strains, and the use of chemosensitizers the rate of permeation/accumulation of fluorescent antimicrobial agents can be followed and measured in bacteria. The respective involvement of influx and efflux in the internal concentration of various molecules and in the bacterial susceptibility can be dissected and compared in various bacterial strains expressing various level of membrane-associated mechanisms of resistance. Combination of activity determination and image analyses open a new field of research in the molecular understanding of resistance mechanisms and in the rational approach of antibacterial chemotherapy. The research leading to the results presented here was conducted as part of the Translocation consortium (www.translocation.eu) and has received support from the Innovative Medicines Initiative joint Undertaking under Grant Agreement n° 115525, resources which are composed of financial contribution from the European Union’s seventh framework program (FP/2007–2013) and EFPIA companies in kind contributions. Keywords Antibiotics, Efflux pumps, Enterobacteriaceae, multidrug resistance, porins, single cell bacterial resolution Relevant publications • Nikaido H and Pagès JM. 2012. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol. Rev. 36(2):340-363. • Kaščáková et al. Antibiotic transport in resistant bacteria: synchrotron UV fluorescence microscopy to determine antibiotic accumulation with single cell resolution. PLoS One. 2012;7(6):e38624. • Pagès et al. New Peptide-based antimicrobials for tackling drug resistance in bacteria: single-cell fluorescence imaging. ACS Med Chem Lett. 2013, 4(6):556-9. • Philippe et al. In vivo evolution of bacterial resistance in two cases of Enterobacter aerogenes infections during treatment with imipenem. PLoS One. 2015 September 23;10(9):e0138828. • Cinquin et al. 2015. Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level. Sci. Reports, 2015. 5, 17968. • Pagès et al. The role of the outer membrane and porins in the susceptibility of β-lactamase-producing Enterobacteriaceae to ceftazidime-avibactam. Antimicrob Agents Chemother. 2015 December 14. pii: AAC.01585-15.