University of Utah
Repurposing old scaffolds as new anti-tubercular leads
While the incidence of tuberculosis (TB) has steeply declined in the U.S., it remains one of the world’s deadliest diseases. Despite this pressing global health crisis, no new TB drug has been developed in almost 50 years and the current curative regimens require lengthy treatment, complicated administration and can be toxic at the doses needed to treat emerging strains of multi-drug and extensively-drug resistant Mycobacterium tuberculosis (Mtb).
TB / HIV co-infection is considerably distressing as most common TB drugs (e.g. rifampin) are strong activators of hepatic cytochromes, rendering highly active anti-retroviral therapy (HAART) used to treat HIV ineffective. The goals of this proposal integrate synthetic and medicinal chemistry, microbiology and structural biology to: 1) Explore a newly identified antibiotic scaffold that acts by inhibiting ribosomal protein synthesis and is compatible with HAART; 2) Shorten TB treatment regimens by disrupting mycobacterial biofilm physiology; and 3) Evaluate these treatments ability to incur resistance.