The prevalence of infections by nontuberculous mycobacteria is increasing, having surpassed tuberculosis in the United States and much of the developed world. Nontuberculous mycobacteria occur naturally in the environment and are a significant problem for patients with underlying lung diseases such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Current treatment regimens are lengthy, complicated, toxic and they are often unsuccessful as seen by disease recurrence. Mycobacterium abscessus is one of the most commonly encountered organisms in nontuberculous mycobacteria disease and it is the most difficult to eradicate. There is currently no systematically proven regimen that is effective for treating M. abscessus infections. Our approach to drug discovery integrates machine learning, medicinal chemistry and in vitro testing and has been previously applied to Mycobacterium tuberculosis. We have now identified several novel 1-(phenylsulfonyl)-1H-benzimidazol-2-amines that have weak activity on M. abscessus in vitro but may represent a starting point for future further medicinal chemistry optimization. We also address limitations still to be overcome with the machine learning approach for M. abscessus.