VRI - Antibiotics
A TREATMENT FOR UNTREATABLE SUPERBUGS™
Severe bacterial infections that are resistant to current anti-bacterial drugs are becoming more frequent. Five to ten percent of patients admitted to hospital in the United States develop some level of hospital-acquired infection. An estimated 90,000 people in the United States died from hospital-acquired infections in 1999 with Staphylococcus aureus infecting about 400,000 United States hospital patients a year.
Therapeutic Potential
The development of bacterial resistance to antibiotics has resulted in continued market opportunities for new compounds which act against resistant strains of bacteria. The present drug of last resort, when all else fails, is vancomycin. However, vancomycin-resistant bacteria are spreading, and there is currently no simple antibiotic treatment for vancomycin-resistant infections, creating a significant unmet medical need that is likely to continue to expand in the future.
Project Status
A series of lead compounds has been generated through molecular modelling and directed medicinal chemistry, and these compounds are presently being optimized using antibacterial assays and molecular modelling techniques to select a lead molecule for preclinical testing.
Scientific Rationale
Resistance to vancomycin occurs when bacteria change such that vancomycin can no longer bind to their cell wall. Rather than search for new compounds against unmodified bacteria in the hope that they might retain activity against resistant bacteria, this project set out to design compounds that actively bind to the modified cell wall in resistant bacteria, using structural information from the vancomycin-resistant cell wall in the design process. This novel approach has required the development of new chemistry to synthesize compounds capable of binding to the modified target (as well as the normal target). These compounds show anti-bacterial activity against both vancomycin sensitive and vancomycin-resistant bacteria, as the compounds can bind to both the normal and the modified (resistant) cell wall.
