This CETR is an interdisciplinary consortium of groups from academia and the pharmaceutical industry, whose goal is to provide a center for development of therapeutic countermeasures against multidrug resistant bacteria as well as select agent pathogens, and to deliver candidates suitable for preclinical evaluation. The role of Core B is to provide pharmacokinetic, toxicological and tissue distribution evaluation during these early phases of drug discovery to (1) assist in hit triage, hit-to-lead progression and lead selection efforts, and (2) reduce the risk of costly failures later in the development process. We propose to leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Regional Biocontainment Lab ofthe PHRI (Newark, NJ) to assist the assembled team in the optimization of hits and leads generated within each project. Relevant in vitro assays and in vivo studies will be integrated to guide rounds of structure-activity relationships in collaboration with the medicinal chemists (Core D). These assays include in vitro ADME evaluation, in vivo pharmacokinetics and tolerability studies in mice, in vitro toxicology assays, and lesion pharmacokinetic studies in relevant murine models and in the rabbit model of TB disease. A state-of-the-art MALDl mass spectrometry imaging platform will allow characterization of lead candidates for their ability to penetrate infected tissues, a question which has been largely neglected so far . in the development of new anti-infectives. Compound prioritization, resource allocation and phase transitions will be based on standard threshold parameters that are in line with industry guidelines. As a rule of thumb, the complete biological, pharmacokinetic and physico-chemical profile ofthe compounds, rather than single 'and rigid cutoff values, will be considered in all decision making processes. The Core B Leader, Veronique Dartois, has extensive experience in the pharmacological profiling of anti-infective compounds, acquired through 7 years in the field of neglected disease drug development.
): Core B in the context of this proposal will speed the discovery and development of multiple new drugs against high-threat multidrug resistant Gram-positive and Gram-negative bacteria, select agent pathogens and multi-drug resistant tuberculosis. Each of these infectious disease areas constitutes a largely unmet medical need of growing concern for global health.
|Chu, John; Vila-Farres, Xavier; Inoyama, Daigo et al. (2016) Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nat Chem Biol 12:1004-1006|
|Perryman, Alexander L; Stratton, Thomas P; Ekins, Sean et al. (2016) Predicting Mouse Liver Microsomal Stability with ""Pruned"" Machine Learning Models and Public Data. Pharm Res 33:433-49|
|Ekins, Sean; Perryman, Alexander L; Clark, Alex M et al. (2016) Machine Learning Model Analysis and Data Visualization with Small Molecules Tested in a Mouse Model of Mycobacterium tuberculosis Infection (2014-2015). J Chem Inf Model 56:1332-43|
|Ekins, Sean; Madrid, Peter B; Sarker, Malabika et al. (2015) Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery. PLoS One 10:e0141076|