Improved Non-Redundant Species Screening Panels for Benchmarking the Performance of New Investigational Antibacterial Candidates Against Category A and B Priority Pathogens

Background:NIAID has a programme for testing drug candidates against biodefense and emerging bacterial pathogens that uses defined strain panels consisting of standard laboratory reference strains and strains of clinical origin.Objectives:The current studies were performed to assess the activity of standard-of-care drugs, determine benchmark criteria for new investigational antibacterial candidate prioritization and identify reduced non-redundant strain panels for candidate performance classification.Methods:The susceptibilities of each strain in the screening panels to 40 standard-of-care drugs and clinical drug combinations were determined by percentage growth inhibition using multiple concentrations, a method commonly used in efficient high-throughput screening efforts. The drug susceptibility of each strain was categorized based on interpretive criteria to benchmark the activity of each standard-of-care drug and drug combination, followed by confirmation of select active drugs. Exact match and clustering analyses defined focused non-redundant species and pan-species screening panels.Results:This process revealed a broad spectrum of susceptibilities among strains in each species, with important differences between the standard laboratory reference strains and strains of clinical origin. Exact match and clustering analyses identified subsets of non-redundant strains that can more efficiently classify drug activity resulting in individual species screening panels, a pan-species screening panel and a pan-species maximum resistance panel.Conclusions:This study resulted in improved non-redundant species screening panels for benchmarking the performance of new investigational antibacterial candidates with the greatest potential for efficacy against clinically relevant Category A and B priority and emerging pathogens.