Research

The continued rise of drug resistance, paired with the decline in newly approved antibiotics for existing targets, has reinvigorated the desire to exploit new antibacterial strategies. We have two major focuses within this arena. One is to identify and exploit new targets in Clostridioides difficile, a leading cause of hospital-acquired illness and is now infiltrating communal living spaces. The second is to identify and develop small molecule modulators that cause detrimental effects to bacteria through pathway or enzyme activation, rather than inhibition. Currently, we are interested in the activation of bacterial proteases (e.g., ClpP) or two-component signaling pathways (e.g., CpxRA).

A major roadblock to the development of novel antibiotics is our poor understanding of the molecular features that correlate with bacterial permeation and accumulation. While potent biochemical inhibitors can often be identified for new targets, developing them into compounds with whole-cell antibacterial activity has proven challenging, especially for Gram-negative pathogens. The development of quantitative tools to predict small-molecule penetration and efflux in Gram-negative bacteria would have a major impact on antibacterial drug discovery, and enable rational approaches to library design and hit-to-lead optimization. In collaboration with researchers at Sloan Kettering, OU, and industry partners we are working to address this need for predictive capability.

Currently, over 400 million people worldwide have diabetes mellitus. Nearly 1/3 of diabetics suffer from diabetic retinopathy (DR), a leading cause of blindness in the global working population. Despite standard treatment options, the ability to address the microvascular component of DR remains a significant challenge. While anti-VEGF therapy has been revolutionary, this mode of intervention suffers from a dependence on iterative injections, low patient response (~60%), high cost, limited access in developing countries, and a heavy burden to healthcare infrastructures. In collaboration with the Oklahoma University Health Science Center, we are developing new therapeutic modalities to address DR and mechanistically related conditions (e.g., age-related macular degeneration and retinopathy of prematurity).