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

Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus.

Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all β-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with β-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin-binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models shows that penicillin/β-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for 'susceptible' MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin but the absence of clavulanic acid, which suggests that penicillin/β-lactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.MRC - G1001787/1 MRC - MR/N002660/1 WT098600 HICF-T5-342 MR/S00291X/1 201344/Z/16/Z MR/P007201/

Chronic Arthritis in Rats; Pathogenesis and genetic factors

The immune pathology and MHC association of chronic arthritis was studied in three rat models for reumatoid arthritis (RA). Susceptible rat strains develop a T cell dependent chronic disease after immunization with rat collagen type II (CII). The LEW rat does not develop arthritis after immunization with rat CII, but a heterologous immune response to pepsin can break the tolerance to CII and render it susceptible to collagen induced arthritis (CIA). DA rats are protected against CIA if pre-treated with denatured CII or native CII in a non arthritogenic fashion. This was associated with a poor B cell response but a normal T cell response compared to that of CIA, suggesting that B cells specific for conformational epitopes on the CII molecule are essential for the development of chronic CIA. The non-immunogenic adjuvants, avridine and pristane induced chronic T cell dependent arthritis in rats. CIA, AvIA and PIA had a similar MHC association, with RT1a and RT1f being the most susceptible haplotypes. In AvIA and PIA, the MHC mainly influenced the chronicity of arthritis. The genetic control of the PIA model, apart from the MHC association (pia1), was further analyzed in a cross between E3 and DA. A total genome scan of the F2 progeny revealed an additional loci; pia2 on chromosome 12 and two suggestive loci pia3 on chromosome 6 and pia4 on chromosome 11. Pia2 and pia4 were also associated with an a1-acid glycoprotein production and an IgG2b and rheumatoid factor response, whereas pia3 was associated with a fibronectin and IL-6 response

How preclinical infection models help define antibiotic doses in the clinic

Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. (C) 2020 The Authors. Published by Elsevier B.V