Drug Discovery

Tuberculosis (TB) is a devastating infectious disease that continues to plague the world, despite improved hygiene, massive vaccination efforts, and an arsenal of chemotherapeutic agents. Mycobacterium tuberculosis (Mtb), the causative agent of TB, is a slow growing bacterium that naturally resists most currently known antibiotics. Emergences of ever-increasing drug-resistant Mtb strains threaten our ability to control the disease. Unfortunately, slow drug development efforts led to the approval of only one new TB drug in the last 50 years by the US Food and Drug Administration. This dismal progress warrants a re-evaluation of approaches and methods for new TB drug discovery. Although successful in the past, the continuous use of in vitro drug discovery methods eroded recent attempts towards TB drug discovery, caused by a pathogen that inhabits human cells. Advances in recent years include the development of new intracellular screening protocols using relevant disease models. Pilot studies have yielded new lead compounds filling the pipeline for further development. Furthermore, these studies have revealed new insights to forecast changes in diagnostics and chemotherapies against this notorious infectious agent. (Zheng and Av-Gay, New era in TB drug Discovery, Curr Treat Options Infect Dis. doi:10.1007/s40506-016-0098-0)

The Av-Gay lab is actively engaged in various drug discovery programs against mycobacterial infections. In collaboration with GSK, we have developed an intracellular HTS assay for finding new anti-TB compounds active in human macrophages. This unique assay enables rapid monitoring of efficacy and toxicity characteristics of candidate inhibitors in a highly sustainable way conducive to industry settings, unlike conventional screening methods. We are currently using an advanced, High Content variation of this assay, for discovery of novel inhibitors within infected macrophages.

In addition, we are conducting HTS against Mycobacterium abscessus, a notorious Non Typical Tuberculosis (NTM) prevalent in CF patients.