Drs. Yang and Chen have synthesized several novel chemical compounds which inhibit the expression of the Type III Secretion System (T3SS) virulence genes of the plant pathogens D. dadantii 3937, P. syringae pv tomato DC3000, and Erwinia amylovora as well as the human pathogen Pseudomonas aeruginosa. The compounds do not affect the viability of the bacteria. The T3S apparatus is not necessary for survival of the pathogenic bacteria; therefore these inhibitors are unlikely to lead to selective pressure and trigger resistance to the compounds in the pathogens. The inhibitors also do not harm normal, non-pathogenic microbial flora. Members of this 101-compound T3SS inhibitor library could be effective therapies against multiple Gram-negative pathogens that commonly affect major crops.
Limited options are available for the control of bacterial disease in plants, animals, and humans. Many commercially available antimicrobials lead to death of the pathogen. This pressure leads to the natural selection of microbes that develop mutations enabling them to resist the compound or drug and survive. Most antimicrobials used for fighting pathogenic bacteria also eliminate beneficial natural microbes. Loss of the natural symbiotic microbes leaves plants more vulnerable to future disease attacks due to a lack of competition against the pathogenic bacteria. Many pathogenic bacteria found in animals and plants utilize a type III secretion system (T3SS) which releases proteins into the host organism that are essential for pathogenesis. The T3SS is an attractive target for the development of antimicrobial compounds, since it is present in numerous plant, human, and animal pathogens, but is not found in their nonpathogenic counterparts.
Plant diseases cause billions of dollars worth of direct and indirect losses every year, but the options for bacterial disease control in plants are limited. The worldwide pesticide industry was $52 billion in 2008, and the market is expected to grow annually at a rate of 7% between 2008 and 2013 (SBI reports). Major cash crops that are affected by bacterial infections include: rice, barley, wheat, tomato, pepper, cabbage, onion, soybean, potato, carrot, lettuce, cucumber, and eggplant. Besides crop protection, antimicrobials are also utilized in agricultural applications such as feed additives, veterinary medicine, and aquaculture. Regulations in food safety have also increased, leading food processors to search for new ways to prevent contamination in their factories (Decision news media SAS). Unfortunately, the non-therapeutic use of antimicrobial compounds is a major factor in the emergence of antimicrobial resistant pathogens worldwide. One human pathogen of great concern is Pseudomonas aeruginosa, an opportunistic pathogen that infects immunocompromised patients, particularly those hospitalized with cancer, cystic fibrosis, and severe burns. The case fatality rate in these patients is near 50 percent. Due to its natural resistance to a broad-range of antibiotics, novel approaches to develop anti-pseudomonal agents are urgently required.
The T3SS inhibitory compounds designed by the inventors specifically target an infectious component of the pathogenic bacteria that is non-essential for normal growth and survival. This feature greatly diminishes the chance of the pathogens acquiring resistance to the compounds. T3S components are conserved in numerous pathogens that infect plants, humans, and animals suggesting a broad range of applications for these compounds. Potential applications include control and prevention of plant disease in agriculture, application on vegetable surfaces to reduce the risk of co-contamination by human pathogens, prevention of post-harvest infection in storage crops, household antimicrobial products, veterinary medicine, and pharmaceuticals.
Ching-Hong Yang, Ph.D.
Xin Chen, PhD.
Eric Toone, Ph.D.
Dr. Ching-Hong Yang is an Associate Professor in the Department of Biological Sciences at University of Wisconsin- Milwaukee specializing in functional genomics and host-microbe interactions. He earned a Ph.D. from the University of California Riverside and was a Postdoctoral fellow at UC Riverside and UC Davis.
Dr. Xin Chen is a Professor of Chemistry in the School of Pharmaceutical & Life Science at Changzhou University.
Dr. Eric Toone is a Professor in the Department of Chemistry at Duke University.
Li Y., Peng Q., Selimi D., Wang Q., Charkowski A.O., Chen X., Yang C.H. (2009) The plant phenolic compound p-coumaric acid represses gene expression in the Dickeya dadantii type III secretion system. Appl Environ Microbiol 75:1223-8.
For further information please contact:
Jessica Silvaggi, Ph.D.
UWM Research Foundation
1440 East North Avenue
Milwaukee, WI 53202
Please reference: OTT ID. 1112/1200
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