Species-specific activity of antibacterial drug combinations

International audienceThe spread of antimicrobial resistance has become a serious public health concern, making once treatable diseases deadly again and undermining breakthrough achievements of modern medicine 1,2. Drug combinations can aid in fighting multi-drug resistant (MDR) bacterial infections, yet, are largely unexplored and rarely used in clinics. To identify general principles for antibacterial drug combinations and understand their potential, we profiled ~3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in 6 strains from three Gram-negative pathogens, Escherichia coli, Salmonella Typhimurium and Pseudomonas aeruginosa. Despite their phylogenetic relatedness, more than 70% of the detected drug-drug interactions are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs targeting different cellular processes, whereas synergies are more conserved and enriched in drugs targeting the same process. We elucidate mechanisms underlying this dichotomy and further use our resource to dissect the interactions of the food additive, vanillin. Finally, we demonstrate that several synergies are effective against MDR clinical isolates in vitro and during Galleria mellonella infections with one reverting resistance to the last-resort antibiotic, colistin

The Cyst-Dividing Bacterium Ramlibacter tataouinensis TTB310 Genome Reveals a Well-Stocked Toolbox for Adaptation to a Desert Environment

Ramlibacter tataouinensis TTB310T (strain TTB310), a betaproteobacterium isolated from a semi-arid region of South Tunisia (Tataouine), is characterized by the presence of both spherical and rod-shaped cells in pure culture. Cell division of strain TTB310 occurs by the binary fission of spherical “cyst-like” cells (“cyst-cyst” division). The rod-shaped cells formed at the periphery of a colony (consisting mainly of cysts) are highly motile and colonize a new environment, where they form a new colony by reversion to cyst-like cells. This unique cell cycle of strain TTB310, with desiccation tolerant cyst-like cells capable of division and desiccation sensitive motile rods capable of dissemination, appears to be a novel adaptation for life in a hot and dry desert environment. In order to gain insights into strain TTB310's underlying genetic repertoire and possible mechanisms responsible for its unusual lifestyle, the genome of strain TTB310 was completely sequenced and subsequently annotated. The complete genome consists of a single circular chromosome of 4,070,194 bp with an average G+C content of 70.0%, the highest among the Betaproteobacteria sequenced to date, with total of 3,899 predicted coding sequences covering 92% of the genome. We found that strain TTB310 has developed a highly complex network of two-component systems, which may utilize responses to light and perhaps a rudimentary circadian hourglass to anticipate water availability at the dew time in the middle/end of the desert winter nights and thus direct the growth window to cyclic water availability times. Other interesting features of the strain TTB310 genome that appear to be important for desiccation tolerance, including intermediary metabolism compounds such as trehalose or polyhydroxyalkanoate, and signal transduction pathways, are presented and discussed

Biais d'ancrage et ajustement sur les décisions judiciaires (effet de l'expertise)

TOULOUSE2-BUC Mirail (315552102) / SudocSudocFranceF

Molecular Biology and Genetic Tools to Investigate Functional Redundancy Among Fe-S Cluster Carriers in E. coli

International audienc

Du fer et du soufre dans les protéines

Les centres fer-soufre (Fe-S) sont des groupements prosthétiques présents dans de très nombreuses protéines chez la plupart des organismes vivants. À titre d’exemple, la bactérie Escherichia coli synthétise plus de 130 types de protéines à centres Fe-S différentes. Les protéines à centres Fe-S sont impliquées dans une grande diversité de processus biologiques, de la respiration à la photosynthèse, et du métabolisme à la régulation de l’expression génique ou à la stabilité génomique. Si l’acquisition des centres Fe-S par les protéines, processus que l’on désigne par le mot de maturation, peut se faire spontanément in vitro, elle nécessite in vivo l’intervention de machineries moléculaires dédiées. Le dysfonctionnement de ces machineries peut conduire à des phénotypes très marqués, de la létalité chez les bactéries à des pathologies graves chez l’homme. Après avoir rappelé les grands principes sous-jacents à la biogenèse des centres Fe-S et à leur incorporation dans les protéines cellulaires, nous illustrerons l’importance de ce processus en décrivant quelques cas de dysfonctionnement de protéines à centre Fe-S et de machineries de biogenèse chez les bactéries et l’homme

Building Fe–S proteins: bacterial strategies

International audienc

Genetic approaches of the Fe–S cluster biogenesis process in bacteria: Historical account, methodological aspects and future challenges

AbstractSince their discovery in the 50's, Fe–S cluster proteins have attracted much attention from chemists, biophysicists and biochemists. However, in the 80's they were joined by geneticists who helped to realize that in vivo maturation of Fe–S cluster bound proteins required assistance of a large number of factors defining complex multi-step pathways. The question of how clusters are formed and distributed in vivo has since been the focus of much effort. Here we review how genetics in discovering genes and investigating processes as they unfold in vivo has provoked seminal advances toward our understanding of Fe–S cluster biogenesis. The power and limitations of genetic approaches are discussed. As a final comment, we argue how the marriage of classic strategies and new high-throughput technologies should allow genetics of Fe–S cluster biology to be even more insightful in the future. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases

Accident vasculaire cérébral aux urgences (comparaison du pronostic entre patients jeunes et patients âgés)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Comparaison de la prise en charge de l'accident vasculaire cérébral aux urgences chez les patients jeunes et âgés (à propos d'une étude réalisée aux urgences de l'hôpital de la Pitié Salpêtrière)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF