The primary research focus in our laboratory is translational research related to the development of new drugs and regimens to improve the treatment of important mycobacterial infections, including tuberculosis (TB), Buruli ulcer and other diseases caused by nontuberculous mycobacteria. We approach the problem using both established and emerging animal and in vitro models of infection and relying on pharmacodynamic principles. Our major goal is to identify and optimize new drugs and drug combinations to shorten and/or simplify treatment and restrict the emergence of drug resistance. Over the past 18 years, we have worked with a variety of public and private sponsors and partners to inform the development of a number of new and repurposed drugs, including moxifloxacin, rifapentine, bedaquiline, pretomanid, sutezolid, and linezolid, as well as novel regimens containing these drugs. We continue to refine existing models and develop new models for pre-clinical drug efficacy studies, including murine models of latent TB infection, cavitary TB and an in vitro “hollow fiber” system for studying the pharmacodynamics of new drugs and combinations.

We are applying similar approaches to improve the treatment of Buruli ulcer and other diseases caused by nontuberculous mycobacteria. Buruli ulcer is a neglected tropical disease characterized by enlarging and ultimately disabling skin ulcers caused by infection with Mycobacterium ulcerans and production of its unique cytotoxin, mycolactone. Only in the last two decades has chemotherapy replaced surgery as the preferred therapeutic option, especially for early lesions. However, early lesions are difficult to detect with available diagnostics and the currently recommended regimens of rifampin combined with either streptomycin or clarithromycin for 8 weeks have many drawbacks. We aim to translate advances in the TB drug development space and novel ideas for detection of mycolactone in biological samples to shorten and simplify treatment and improve point-of-care diagnostics. Pulmonary disease caused by nontuberculous mycobacteria, including Mycobacterium avium complex and Mycobacterium abscessus complex, is notoriously difficult to treat, and there are limited tools available for preclinical evaluation of new treatment options. We are working to repurpose existing antibiotics and, with the Global Alliance for TB Drug Development, to discover new, more effective drugs against these opportunistic pathogens and to develop superior in vitro and mouse model systems for evaluating their activity in novel regimens.