Redx Anti-Infectives, Ltd.

Antimicrobial resistance is a global issue, and the investigation of alternative therapies that are not traditional antibiotics are warranted. Novel bacterial type II topoisomerase inhibitors (NBTIs) have recently emerged as a novel class of antibiotics with reduced potential for cross-resistance to fluoroquinolones due to their novel mechanism of action. This study investigated the in vitro activity of a series of cyclohexyl-oxazolidinone bacterial topoisomerase inhibitors against type strains of Francisella tularensis and Burkholderia pseudomallei. Broth microdilution, time-kill, and cell infection assays were performed to determine activity against these biothreat pathogens. Two candidates were identified that demonstrated in vitro activity in multiple assays that in some instances was equivalent to ciprofloxacin and doxycycline. These data warrant the further evaluation of these novel NBTIs and future iterations in vitro and in vivo.

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.

Since its introduction into the drug-development arena, accelerator mass spectrometry (coupled with liquid chromatography fractionation) has been used to support a variety of study types. The uses to which the technique has been put include parent and/or metabolite quantification in pharmacokinetic studies, total radioactivity measurement in adsorption, metabolism and excretion studies, and quantitative metabolite profiling. A tiered approach has been applied to the verification of accelerator mass spectrometry assays, dependant on in which type of study and at what stage of drug development they are used. As accelerator mass spectrometry is an absolute detector that can quantify without the use of analyte-related standards, the specific assay verification requirements differ from those for LC–MS/MS assays. This article describes when screening, qualified and validated assay verification procedures should be applied, and suggests what parameters should be assessed in each case.