Day 1 :
Julie Bouckaert, Université de Lille, France
Julie Bouckaert is associated with Université de Lille, France. She has published several papers in reputed journals. She is committed to highest standards of excellence and is proved through her authorship of many books. Her research interests include Systems Biology, Molecular Biology and Microbiology.
Shear force exerted on uropathogenic Escherichia coli adhering to surfaces makes type-1 fimbriae stretch out like springs to catch on to mannosidic receptors. This mechanism is initiated by a disruption of the quaternary interactions between the lectin and the pilin of the two-domain FimH adhesin and transduces allosterically to the mannose-binding pocket of FimH to increase its affinity. Shear stress protects Escherichia coli cells adhering to surfaces via catch bonds from detachment by soluble inhibitors present in urine. Mannose-specific adhesion of 14 E. coli pathovars was measured under flow, using surface plasmon resonance detection on functionalized graphene-coated gold interfaces. Increasing the shear had important differential consequences on bacterial adhesion. Adherent-invasive E. coli, isolated from the feces and biopsies of Crohn’s disease patients, consistently changed their adhesion behavior less under shear and displayed lower SPR signals, compared to E. coli opportunistically infecting the urinary tract, intestines or loci of knee and hip prostheses. We exemplified this further with the extreme behaviors of the reference strains UTI89 and LF82. Whereas their FimA major pilins have identical sequences, FimH of LF82 E. coli is marked by the Thr158Pro mutation. Positioned in the inter-domain region known to carry hot spots of mutations in E. coli pathotypes, residue 158 is indicated to play a structural role in the allosteric regulation of type-1 fimbriae-mediated bacterial adhesion. In a next stage, we plan to investigate structure-function relationships of FimH using several mannosylated protein receptors and antagonists immobilized on graphene or supplied in solution and interacting with E. coli strains under varying flow conditions.
Massachusetts Institute of Technology, USA
Keynote: Metal homeostasis and infectious disease: siderophore-based strategies to inhibit growth of bacterial pathogens
Time : 11:15-11:55
Elizabeth M Nolan is an Associate Professor of Chemistry at the Massachusetts Institute of Technology. Her current research interests address the bioinorganic chemistry of infectious disease and the host-microbe interaction, and include investigations of metal homeostasis, host-defense factors, and bacterial metabolites.
New strategies to treat bacterial infections and counteract the emergence of antibiotic resistance are needed. Metal ions are essential nutrients for all organisms, and almost all bacterial pathogens have a metabolic iron requirement. Thus, these microbes must acquire iron from the mammalian host to replicate and cause disease. Many bacteria biosynthesize and utilize siderophores, secondary metabolites that coordinate iron(III) with high affinity, to scavenge iron from the host. The proteins required for the biosynthesis and transport of these iron-chelating metabolites are expressed under iron-limited conditions. Siderophores are considered to be virulence factors and the notion of employing siderophore and siderophore mimics, as well as targeting siderophore biosynthesis and transport machineries, has attracted significant interest for antibiotic development over many years. Here, we first present vignettes from our studies of siderophore-mediated targeting of small molecule antibiotics to Gram-negative bacteria. We report that siderophore-antibiotic conjugates based on native siderophore platforms allow broad-spectrum antibiotics like b-lactams to be targeted to specific bacterial populations, particularly Gram-negative pathogens, on the basis of siderophore receptor expression. For instance, salmochelin-antibiotic conjugates kill Escherchia coli that express the salmochelin receptor iron, including uropathogenic strains, but not E. coli that lack this receptor. In a related thrust, we describe our recent efforts to block iron acquisition by gastrointestinal pathogens using siderophore-based immunization. We report that immunization of mice with CTB-Ent, a conjugate of cholera toxin subunit B and the siderophore enterobactin is well-tolerated, results in generation of antisiderophore antibodies in the gut, and provides protection against Salmonella enterica serovar Typhimurium in a mouse model of infection. Together, these fundamental studies support the notion that hijacking siderophore uptake pathways and blocking siderophore-based iron acquisition may provide new opportunities for new strategies to prevent and treat infectious diseases.