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Mycobacterium abscessus  is a non-tuberculous mycobacterium that causes pulmonary and non-pulmonary infections.  M. abscessus  is resistant to many chemotherapeutic agents and the current treatment options show poor clinical outcomes. Thus, there is a dire need to find new antimicrobials effective at killing  M. abscessus . Screening drug libraries to identify potential antimicrobials has been impeded by the lack of validated HTS assays for  M. abscessus . In this study, we developed two 384-well high-throughput screening assays using fluorescent and bioluminescent reporter strains of  M. abscessus  for drug discovery. Optimization of inoculum size, incubation time and the volume-per-well based on Z-factor and signal intensity yielded two complementary, robust tools for  M. abscessus  drug discovery with Z-factor > 0.8. The MIC of known drugs, amikacin and clarithromycin, as determined by bioluminescence was in agreement with the published MIC values. A proof-of-concept screen of 2,093 natural product-inspired compounds was conducted using the 384-well bioluminescent assay to identify novel scaffolds active against  M. abscessus.  Five active “hit” compounds identified in this pilot screen were confirmed and characterized by a CFU assay and MIC determination. Overall, we developed and validated a 384-well screen that offers simple, sensitive and fast screening of compounds for activity against this emerging pathogen. To our knowledge, this is the first reporter–based high-throughput screening study aimed at  M. abscessus  drug discovery.

Reporter-Based Assays for High-Throughput Drug Screening against Mycobacterium abscessus