Therapeutic: Antibacterial

Background

Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for nearly two million deaths annually. Moreover, the emergence of multidrug-resistant (MDR) strains of Mtb seriously threatens TB control and prevention efforts.  M. tuberculosis is recognized to lie in a non-replicating state (dormancy), particularly in the caseous nodules of the lungs where the lesions have little access to oxygen, and can survive for many years in the host by entering a dormant state. Reactivation is a concern for patients with latent Mtb.  Thus, in addition to the necessity of drugs for the treatment of MDR-Mtb, the development of drugs that kill Mtb in any state is very important. However, no current TB drugs are effective in killing the dormant form of Mtb in vivo.

The Technology

Aurachin RE is a strong antibiotic that was recently found to possess MenA (1,4-dihydroxy-2-naphthoate prenyltransferase) and bacterial electron transport inhibitory activities. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of molecules were designed by mimicking the structure of aurachin RE, and the synthesized molecules were evaluated in in vitro assays including MenA enzyme and bacterial growth inhibitory assays. A series of MenA inhibitors identified in this program exhibited antimicrobial spectrum focused against Mtb. Selective activity against Mtb is ideal in TB drug discovery due to the fact that TB chemotherapy requires a long regimen, so that broad-spectrum anti-TB agents may cause resistant to other bacteria during TB chemotherapy. These new MenA biosynthesis inhibitors showed very weak (or no) inhibitory activities of bacterial electron transport systems and showed a significant increase in potency of killing non-replicating M. tuberculosis in the low oxygen recovery assay without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against non-replicating M. tuberculosis.  In vivo evaluation of these novel compounds is ongoing.

·         Novel and selective MenA inhibitors against M. tuberculosis

·         Lead molecule MICs: 2.31 mg/mL (M. tuberculosis, MABA); 0.85 mg/mL (M. tuberculosis, LORA);  >60 mg/mL (S. aureus); significant growth inhibitory activities against non-replicating Mtb (0.85 mg/mL) MIC_LORA/MIC_MABA value of 0.37, SI >10 (MIC_LORA/MIC_MABA = 7.35 for rifampin)

·         Compounds can be synthesized in short steps with high yield

·         Robust in vitro assay

The Inventor

Dr. Michio Kurosu joined the UT College of Pharmacy faculty in January 2011 as an Associate Professor in the Department of Pharmaceutical Sciences. His research focuses on medicinal chemistry and synthetic organic chemistry involving compounds to treat drug-resistant pathogens, novel cancer chemotherapies, and biologically active natural products.  Dr. Kurosu received his PhD in 1995 from the College of Pharmaceutical Sciences at Osaka University in Japan. Prior to joining UT, he was a faculty member at Colorado State University.

Patents

• PCT/US2013/024290

Publications

Discovery of Selective Menaquinone Biosynthesis Inhibitors against Mycobacterium tuberculosis, Debnath, J.; Siricilla, S.; Wan, B.; Crick, D. C.; Lenaerts, A. J.; Franzblau, S. G.; Kurosu, M. J. Med. Chem. 2012, 55, 3739-3755.