NU 2014-182B
INVENTORS
SHORT DESCRIPTION
New antibacterial compounds targeting bacterial nitric oxide synthase show promise against resistant bacterial strains.
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections. Furthermore, rates of morbidity and mortality are high among those infected. Recent experiments in S. aureus, B. anthracis and B. subtilis have implicated bacterial nitric oxide synthase (bNOS) as a potential drug target, as it provides the bacterial cell a protective defense mechanism against oxidative stress and select antibiotics. While bNOS and mammalian NOS (mNOS) enzymes bear similarity in their active sites, recent studies suggest that bNOS specificity can be achieved by exploiting significant differences in bNOS pterin-binding and mNOS pterin binding sites. Northwestern scientists have identified and characterized nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. High-throughput analysis of a variety of NOS inhibitors identified two potent and chemically distinct bNOS inhibitors and both compounds were found to function as antimicrobials against S. aureus. Both compounds bind well to bNOS and exhibit antimicrobial activity as well as promising bNOS selectivity over mNOS isoforms. These results provide the first evidence that NOS inhibitors have the potential to work synergistically with antibiotic-induced oxidative stress to enhance MRSA killing and offer a structural basis for generating other compounds active against this deadly bacterium.
APPLICATIONS
ADVANTAGES
PUBLICATIONS
Holden J, Kang S, Hollingsworth S, Li H, Lim N, Chen S, Huang H, Xue F, Tang W, Silverman R, Poulos T (2015) Structure-Based Design of Bacterial Nitric Oxide Synthase Inhibitors. Journal of Medicinal Chemistry. 58(2): 994-1004.
IP STATUS
Issued US Patents 9,951,014 and 10,759,791