Dr. Graham Moran and collaborators have shown that 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) decreases pigment production in the bacterium B. cenocepacia and aids in phagolysosomal fusion in macrophages infected with this bacteria in vitro. The researchers have shown that treatment of a pigmented strain of Pseudomonas aeruginosa with NTBC decreases the resistance of both planktonic cells and biofilms to oxidative stress. In preliminary data, NTBC administration also prevented death in mice infected with Pseudomonas aeruginosa versus untreated mice. These results further support the potential use of NTBC in the treatment of microbial infections. Originally developed for herbicide use, NTBC is approved by the FDA for the treatment of specific rare inherited metabolic defects. The mechanism of action is based on the inhibition of an enzyme known as 4-hydroxyphenylpyruvate dioxygenase (HPPD).
Many infectious bacteria and fungi alter their metabolism in response to the elevated temperature of their host. One way in which some of these pathogens act is through the HPPD pathway. They produce a pigment known as pyomelanin, which is made directly from a product of the HPPD reaction. It is thought that pathogenic bacteria and fungi use pyomelanin and other melanins to suppress the efficiency of the host's initial immune response. Thus, inhibition of these pigments may aid in fighting infection.
Microbial infections can either be superficial (affecting skin, nails, hair, and mucous membranes) or systemic (entering the bloodstream and affecting internal organs or the nervous system). Systemic infections can be caused by an invasive organism common to a specific geographic area or an opportunistic organism that attacks those with a weakened immune system. Some people who are at a greater risk for systemic infections include cancer patients, AIDS patients, diabetes patients, those taking corticosteroids, and organ transplant patients. The structure and chemical make-up of fungi can make them difficult to kill. Other difficulties with fungal infections include drug resistant fungi, early and correct diagnosis, and lack of success with single drug treatments. Bacterial infections have become increasingly problematic due to multiple drug resistant strains.
The antifungals market was estimated at $7.4 billion in 2009 by Research and Markets. The market is expected to grow to $8.4 billion by 2016. There remains significant unmet need due to low spectrum activity of commercial drugs, unfavorable interactions with other medications, toxicity problems, and fungal resistance issues. The antibacterial market is predicted by Visiongain to reach $43.8 billion by 2016. Antibiotic resistance continues to complicate bacterial infections and nosocomial infections remain a major burden on the health care budgets in developed and developing countries.
NTBC has great potential for antifungal and antibacterial treatments both for systemic and superficial infections. With FDA approval already completed, NTBC will be an ideal candidate for combination therapies with other commercial antimicrobial agents. The excellent toxicity profile and long half life in humans after oral ingestion are further advantages of this drug. Other applications include formulations for topical treatments in humans and treatment of animals in veterinary or farm livestock practices.
Graham R. Moran
Dr. Graham Moran is an Associate Professor in the Department of Chemistry and Biochemistry at the University of Wisconsin-Milwaukee. He obtained his Ph.D. in 1996 in Protein Chemistry from the University of Michigan and conducted postdoctoral work at Texas A&M University. In 2008 Dr. Moran received a UWM Research Foundation Catalyst Grant sponsored by the Lynde and Harry Bradley Foundation for his work on novel treatments for fungal infections.
For further information please contact:
Jessica Silvaggi, Ph.D.
UWM Research Foundation
1440 East North Avenue
Milwaukee, WI 53202
Please reference: OTT ID. 1133
This technology is part of an active and ongoing research program and is seeking partners for development of the final product. It is available for developmental research support/licensing under either exclusive or non-exclusive terms.