Synergistic activity of sulbactam combined with colistin against colistin-resistant Acinetobacter baumannii

Acinetobacter baumannii is an emerging multidrug-resistant (MDR) pathogen that is responsible for community- and hospital-acquired infections that are difficult to control and treat [1]. With increasing antimicrobial resistance to carbapenems, colistin is often the treatment of last resort, however colistin-resistant clinical isolates have already been reported. Since therapeutic options are very limited or absent in some cases of infection with pandrug-resistant bacteria, there is an urgent need to find new antibiotic strategies

Synthesis of new 3,20-bis (polyaminosteroid) derivatives and evaluation of their antimicrobial activities. Application in human therapeutics

Les dérivés aminostéroïdiens analogues de la squalamine ont été largement étudiés pour leur large spectre d’activité sur les bactéries et les champignons multirésistants. Nous avons réalisé la synthèse de nouveaux dérivés aminostéroïdiens et présentant de nombreuses charges positives liées à la présence de groupements azotés, les 3,20-bis(polyaminostéroïdes) analogues de la squalamine. Une étude de la relation structure-activité a démontré l’importance des charges positives induites par la présence d’atomes d’azote dans les chaines carbonées portées par le motif cholestane. Nous avons mis en évidence les mécanismes d’action mis en oeuvre vis-à-vis des bactéries Gram positive et Gram négative. L’étude des activités antifongiques démontre que la squalamine et le dérivé aminostéroïdien DAS-1 possèdent de bonnes activités sur diverses souches de levures impliquées dans de nombreuses fongémies, avec des CMIs variant de 1 à 16 μg/mL. Nous avons étudié les applications potentielles de ces dérivés et démontré que ces dérivés en formulation de pommades à 1% de squalamine et de dérivé 3.20-bis(polyaminostéroïdien) étaient capables de réduire efficacement la colonisation cutanée à S. aureus sur un modèle animal. Il a été démontré que ces dérivés bis(polyaminostéroïdiens) sont également très actifs vis-à-vis de bactérie et de champignons multirésistants isolés des patients mucoviscidosiques. Nous avons testé leur activité en tant qu’agent désinfectant de matériel médical et plus particulièrement les nébuliseurs. La formation de cachets hydrosolubles à base de squalamine, nous a permis de développer un modèle de désinfection simple, rapide et peu onéreux des nébuliseurs contaminés.Aminosterol derivatives analogues of squalamine possess a broad spectrum activity against multidrug resistant bacteria and fungi. We synthesized a new series of 3,20-bis(polyaminosteroïd) analogues involving a titanium reductive amination possessing numerous positives charges due to the presence of nitrogen groups. The study of relation structure-activity demonstrates that the nature of the amino group attached to the sterol plays a crucial role on antimicrobial activity of these compounds. We had also determined the mechanism of action of bis(polyaminosteroïd) on Gram negative and Gram positive bacteria. The study of antifungal activity of squalamine and aminosterol derivative ASD-1 show a good activity against various yeast responsible of fungal infections, minimal inhibitrice concentration ranging from 1 to 16 μg/mL. We studied a potential application of these compounds in human therapeutic. We evaluated squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. Using this model we found that squalamine ointment (1%) was able to reduce efficiently S. aureus colonization. Squalamine and bis(polyaminosteroïd) derivatives were actives against multidrug resistant bacteria and fungi isolated from cystic fibrosis patients. We investigated the potential use of squalamine compound in vitro in a nebulizer disinfection model. A formulation of squalamine disinfecting soluble tablets at 2.5 % (W/W) was developed and successfully applied for rapid nebulizer disinfection

Synthesis of New 3,20-Bispolyaminosteroid Squalamine Analogues and Evaluation of Their Antimicrobial Activities

International audience3,20-Amino- and polyaminosteroid analogues of squalamine and trodusquemine were synthesized involving a stereoselective titanium reductive amination reaction in high chemical yields in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against references and clinical bacterial strains exhibiting minimum inhibitory concentrations of 2.5-40 mu g/mL. The mechanism of action of these derivatives was determined using bioluminescence for ATP efflux measurements and fluorescence methods for membrane depolarization assays

Diastereoselective Synthesis of Potent Antimalarial Cis-β-lactam Agents

International audienceFifteen novel β-lactams bearing N-ethyl tert-butyl carbamate group 5a-o and fifteen N-(2-aminoethyl) β-lactams 6a-o were synthesized by [2+2] ketene-imine cycloaddition reaction (Staudinger). The cycloaddition reaction was found to be totally diastereoselective leading exclusively to theformation of cis-β-lactam derivatives. These newly synthesized β-lactams were evaluated for their antimalarial activity against p. falciparum K14 resistant strain and showed good to excellent EC 50 values. Of the thirty β-lactams tested, 5 h, 6a and 6c showed IC 50 < 20 µM while 5b, 5c, 5e, 5f, 5g, 5i, 5j, 6d, 6g and 6h exhibited IC 50 <50. Compounds 5c, 5h, and 5q-t were examined for their anticancer properties against K562 Leukemia cell line and 5s showed the best activity. Compounds 3a-j, 5a-o, 6a-o, were tested against S. aureus , E. coli, C. albicans and showed no activity below 125 µg/mL

Synergistic activity of sulbactam combined with colistin against colistin-resistant Acinetobacter baumannii

International audienceNo abstract availabl

Synthèse et évaluation des activités antimicrobiennes de nouveaux dérivés 3,20-bis (pollyaminostéroïdiens). Applications en thérapeutique humaine

Les dérivés aminostéroïdiens analogues de la squalamine ont été largement étudiés pour leur large spectre d activité sur les bactéries et les champignons multirésistants. Nous avons réalisé la synthèse de nouveaux dérivés aminostéroïdiens et présentant de nombreuses charges positives liées à la présence de groupements azotés, les 3,20-bis(polyaminostéroïdes) analogues de la squalamine. Une étude de la relation structure-activité a démontré l importance des charges positives induites par la présence d atomes d azote dans les chaines carbonées portées par le motif cholestane. Nous avons mis en évidence les mécanismes d action mis en oeuvre vis-à-vis des bactéries Gram positive et Gram négative. L étude des activités antifongiques démontre que la squalamine et le dérivé aminostéroïdien DAS-1 possèdent de bonnes activités sur diverses souches de levures impliquées dans de nombreuses fongémies, avec des CMIs variant de 1 à 16 &#956;g/mL. Nous avons étudié les applications potentielles de ces dérivés et démontré que ces dérivés en formulation de pommades à 1% de squalamine et de dérivé 3.20-bis(polyaminostéroïdien) étaient capables de réduire efficacement la colonisation cutanée à S. aureus sur un modèle animal. Il a été démontré que ces dérivés bis(polyaminostéroïdiens) sont également très actifs vis-à-vis de bactérie et de champignons multirésistants isolés des patients mucoviscidosiques. Nous avons testé leur activité en tant qu agent désinfectant de matériel médical et plus particulièrement les nébuliseurs. La formation de cachets hydrosolubles à base de squalamine, nous a permis de développer un modèle de désinfection simple, rapide et peu onéreux des nébuliseurs contaminés.Aminosterol derivatives analogues of squalamine possess a broad spectrum activity against multidrug resistant bacteria and fungi. We synthesized a new series of 3,20-bis(polyaminosteroïd) analogues involving a titanium reductive amination possessing numerous positives charges due to the presence of nitrogen groups. The study of relation structure-activity demonstrates that the nature of the amino group attached to the sterol plays a crucial role on antimicrobial activity of these compounds. We had also determined the mechanism of action of bis(polyaminosteroïd) on Gram negative and Gram positive bacteria. The study of antifungal activity of squalamine and aminosterol derivative ASD-1 show a good activity against various yeast responsible of fungal infections, minimal inhibitrice concentration ranging from 1 to 16 &#956;g/mL. We studied a potential application of these compounds in human therapeutic. We evaluated squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. Using this model we found that squalamine ointment (1%) was able to reduce efficiently S. aureus colonization. Squalamine and bis(polyaminosteroïd) derivatives were actives against multidrug resistant bacteria and fungi isolated from cystic fibrosis patients. We investigated the potential use of squalamine compound in vitro in a nebulizer disinfection model. A formulation of squalamine disinfecting soluble tablets at 2.5 % (W/W) was developed and successfully applied for rapid nebulizer disinfection.AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram-Negative Bacteria

International audienc

Development of a skin colonization model in gnotobiotic piglets for the study of the microbial ecology of meticillin-resistant Staphylococcus aureus ST398.

AIMS: Meticillin-resistant Staphylococcus aureus (MRSA) ST398 continues to spread amongst pigs and other domestic animals and man. This highlights the need for models to examine MRSA colonization and investigate control strategies. This study aimed to develop a gnotobiotic pig model and assess the potential of bacterial interference from selected coagulase-negative staphylococci (CNS) against MRSA ST398. METHODS AND RESULTS: Groups of 2-week-old piglets were atraumatically inoculated either with MRSA and/or CNS. Skin and mucosae were swabbed, and bacterial counts compared over a period of 21 days. Piglets developed healthily, and bacterial populations increased similarly for both MRSA and CNS until day 32. On day 37, MRSA counts in groups with CNS reduced significantly compared with MRSA alone (P = 0·03). CONCLUSIONS: The results showed that inoculation of piglet skin with MRSA resulted in spontaneous colonization and that MRSA ST398 has a low pathogenic potential in gnotobiotic piglets. Quantitative bacteriology indicated that initial MRSA colonization was unaffected by concurrent CNS colonization but that interference may occur over a longer period. SIGNIFICANCE AND IMPACT OF THE STUDY: Gnotobiotic piglets provide a reproducible model suitable for bacterial interference studies, which should be further explored as an alternative to antimicrobials in the control of MRSA