In vitro and in vivo characterization of noso-502, a novel inhibitor of bacterial translation

Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem- resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum β-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED50) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile

Optimisation pharmacologique de nouveaux inhibiteurs de la transcritpion procaryote

La spectaculaire augmentation des résistances aux antibiotiques pendant les deux dernières décennies souligne le besoin de classes complètement nouvelles d'agents antibactériens. A cette fin, les récentes avancées dans l'étude de l'ARN polymérase procaryote, une enzyme essentielle pour la synthèse d'ARN à partir d'ADN, ouvre de nouvelles opportunités pour découvrir de telles molécules. Notre équipe a ainsi découvert une nouvelle famille synthétique d'inhibiteurs de cette enzyme. Nous avons alors entrepris une étude de relations structure-activité de ces molécules. Nous nous sommes intéressés à leur faculté à inhiber la transcription et la croissance bactérienne, y compris sous forme de biofilm, ainsi qu'à leur propension à se lier aux protéines sériques, un critère important dans une perspective de développement pharmacologique. Ces nouveaux antibactériens ont montré un potentiel promotteur contre les pathogènes de type Gram-positif.MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Novel peptide derivates as Antibiotics

Novel peptide derivates as Antibiotic

Novel peptide derivates as Antibiotics

Novel peptide derivates as Antibiotic

In Vitro Activities of Different Inhibitors of Bacterial Transcription against Staphylococcus epidermidis Biofilm▿

Staphylococcus epidermidis is a major cause of nosocomial infections because of its ability to form biofilms on the surface of medical devices. Only a few antibacterial agents are relatively active against biofilms, and rifampin, a transcription inhibitor, ranks among the most effective molecules against biofilm-related infections. Whether this efficacy is due to advantageous structural properties of rifampin or to the fact that the RNA polymerase is a favorable target remains unclear. In an attempt to answer this question, we investigated the action of different transcription inhibitors against S. epidermidis biofilm, including the newest synthetic transcription inhibitors. This comparison suggests that most of the antibiotics that target the RNA polymerase are active on S. epidermidis biofilms at concentrations close to their MICs. One of these compounds, CBR703, despite its high MIC ranks among the best antibiotics to eradicate biofilm-embedded bacteria

Progress in targeting bacterial transcription.

The bacterial RNA polymerase (RNAP) is an essential enzyme that is responsible for making RNA from a DNA template and is targeted by several antibiotics. Rifampicin was the first of such antibiotics to be described and is one of the most efficient anti-tuberculosis drugs in use. In the past five years, structural studies of bacterial RNAP and the resolution of several complexes of drugs bound to RNAP subunits have revealed molecular details of the drug-binding sites and the mechanism of drug action. This knowledge opens avenues for the development of antibiotics. Here these drugs are reviewed, together with their mechanisms and their potential interest for therapeutic applications

Use of a surface plasmon resonance method to investigate antibiotic and plasma protein interactions.

International audienceThe pharmacologic effect of an antibiotic is directly related to its unbound concentration at the site of infection. Most of the commercial antibiotics have been selected in part for their low propensity to interact with serum proteins. These "non-specific" interactions are classically evaluated by measuring the minimal inhibitory concentration in the presence of serum. As higher throughput technologies tend to lose information, surface plasmon resonance (SPR) is emerging as an informative medium-throughput technology for hit validation. Here we show that SPR is a useful automatic tool to quantify the interaction of model antibiotics with serum proteins, and delivers precise real-time kinetic data on this critical parameter

The antibiotics in the chemical space.

International audienceEnsuring the availability of new antibiotics to eradicate resistant pathogens is a critical issue, but very few new antibacterials have been recently commercialized. In an effort to rationalize their discovery process, the industry has utilized chemical library and high-throughput approaches already applied in other therapeutical areas to generate new antibiotics. This strategy has turned out to be poorly adapted to the reality of antibacterial discovery. Commercial chemical libraries contain molecules with specific molecular properties, and unfortunately systemic antibacterials are more hydrophilic and have more complex structures. These factors are critical, since hydrophobic antibiotics are generally inactive in the presence of serum. Here, we review how the skewed distribution of systemic antibiotics in chemical space influences the discovery process

Structure-activity relationships of phenyl-furanyl-rhodanines as inhibitors of RNA polymerase with antibacterial activity on biofilms.

The dramatic rise of antibiotic-resistant bacteria over the past two decades has stressed the need for completely novel classes of antibacterial agents. Accordingly, recent advances in the study of prokaryotic transcription open new opportunities for such molecules. This paper reports the structure-activity relationships of a series of phenyl-furanyl-rhodanines (PFRs) as antibacterial inhibitors of RNA polymerase (RNAP). The molecules have been evaluated for their ability to inhibit transcription and affect growth of bacteria living in suspension or in a biofilm and for their propensity to interact with serum albumin, a critical parameter for antibacterial drug discovery. The most active of these molecules inhibit Escherichia coli RNAP transcription at concentrations o