The Chang lab conducts biomedical research to understand the molecular basis of disease and to design small molecules for therapeutic intervention. Some of our current projects are:
Chronic wounds are a complication of diabetes that results in >70,000 lower-limb amputations in the United States every year. The reasons why diabetic wounds are recalcitrant to healing are not fully understood. There is a single FDA-approved drug to treat diabetic foot ulcers; however, it is associated with increased mortality and cancer. We used an affinity resin that binds only the active forms of MMPs (matrix metalloproteinase) and related ADAMs (a disintegrin and metalloproteinase) coupled with quantitative proteomics to identify active MMP-8 and MMP-9 in diabetic wounds. Using the selective MMP-9 inhibitor ND-336 led to acceleration of wound healing by lowering inflammation, enhancing angiogenesis, and re-epitheliazation of the wound, thereby reversing the pathological condition. The role of MMP-9 was confirmed with diabetic MMP-9-knockout mice. Furthermore, the beneficial role MMP-8 in wound healing was determined with a selective MMP-8 inhibitor and by topical application of the proteinase MMP-8. The combined topical application of ND-336 (a small molecule) and active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds condiserable promise in healing of diabetic wounds. We are currently identifying and quantifying active MMPs in patients with diabetic foor ulcers.
Another project involves the design, syntheses, and evaluation of novel antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. diff.) infections. We have identified novel classes of antibacterials. The quinazolinones are active in vivo against MRSA and have an unprecedented mechanism of action, binding to the allosteric site of PBP2a and triggering conformational changes that result in opening of the active site of PBP2a. The oxadiazoles are bactericidal, exhibit efficacy comparable or better to that of linezolid in mouse peritonitis and neutropenic thigh models of infection, have excellent pharmacokinetic properties, synergize with β-lactam antibiotics, and exhibit a long postantibiotic effect. We are currently optimizing the oxadiazoles to impart in vivo C. diff. activity.
