This invention comprises a family of novel antibacterial compounds having a mechanism of action that is distinct from existing antibiotics. At a time when multidrug-resistant (MDR) bacteria represent a serious, ongoing threat to global public health, these compounds potentially offer a critical new line of defense against bacterial infections.
The compounds target the adenylation enzymes required for the biosynthesis of siderophores, small molecules that help acquire essential iron from the human host. By inhibiting the iron-uptake systems of pathogenic bacteria, treatment with these compounds results in reduced bacterial growth in culture.
In animal studies, treatment with the lead compound reduced the growth of bacteria in the lungs of mice that were infected with tuberculosis. In biochemical studies, the lead compound potently inhibited the target enzyme in Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague respectively. Furthermore, treatment with the lead compound inhibited siderophore production and growth of Mycobacterium tuberculosis.
- Novel mechanism of action provides the ability to target drug-resistant pathogens
- Since compounds target an enzyme only found in bacteria, they are anticipated to have fewer off-target effects on mammalian cel
Thanks to its novel mechanism of action, this family of compounds may help to address the mounting threat of multi-drug resistant bacteria, including the life-threatening Methicillin-resistant Staphylococcus aureus (MRSA), and the ESKAPE pathogens, now responsible for about 40% of all hospital-acquired infections. These compounds also may prove a better alternative to current treatments for tuberculosis, which results in 1.3 million deaths annually and expenditures projected to grow to $4.4 billion by 2015.
Derek S. Tan, PhD, Laboratory Head, Molecular Pharmacology & Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering
U.S. patent issued: 8,461,128
Proof of concept established with TB. Lead optimization and animal studies ongoing.