Joan & Sanford Weill Medical College of Cornell University

Start : March 2015 | Status : Complete

The scientist: Dr. Kaj Kreutzfeldt will focus her research on the discovery of new drugs for Tuberculosis (TB), through a project titled "Studies towards the identification of orally available beta-lactams with efficacy against Mycobacterium tuberculosis”. Kaj is a postdoctoral fellow at the Joan & Sanford Weill Medical College of Cornell University with Prof. Sabine Ehrt, and has extensive experience in host-pathogen interactions with a particular focus on mycobacterial infections and the resulting host immune responses.

The sponsor: Weill Cornell Medical College is among the top-ranked clinical and medical research centers in the US. The mission of the Medical College is to provide the finest education possible for medical students and students pursuing advanced degrees in the biomedical sciences, to enable them to conduct research at the cutting edge of knowledge and improve the health care of the nation and the world. Dr. Sabine Ehrt’s laboratory at Weill Cornell Medical College investigates the molecular mechanisms that allow Mycobacterium tuberculosis to establish and maintain persistent infections. Genetic strategies are applied to characterize host-pathogen interactions, identify proteins that help the pathogen resist eradication by the immune system and identify and validate new targets for TB chemotherapy.

Foundation funding: The Foundation is providing £139,000 in support.

GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise for in vitro and in vivo characterization of Mycobacterium tuberculosis (Mtb), access to Biosafety Level 3 facilities and access to GSK´s compounds.

Project Description: TB remains a major public health threat and new drugs that shorten the current TB treatment regimen and cure both, drug sensitive and resistant TB, are needed to reduce the impact of this disease on global health. One of the most important classes of antibiotics for the treatment of bacterial infections are beta-lactam antibiotics, which also represent a major fraction of the global antibiotic market. However, beta-lactams have not been broadly used for treatment of TB, because Mtb produces a broad-spectrum beta-lactamase (BlaC) rendering it resistant to beta-lactams and the organism is protected by a relatively impermeable cell envelope. Nevertheless, the interest in beta-lactams for the treatment of Mtb infections has been renewed by the demonstration of irreversible inactivation of Mtb’s beta-lactamase BlaC by clavulanic acid. Additionally, a mounting body of anecdotal clinical evidence points towards a potential role of beta-lactams in combination therapy. Determining the efficacy of beta-lactams in a rodent animal model has been challenging. Hence,the ability to characterize orally available beta-lactams in a TB mouse model and the identification of compounds that synergize with orally available beta-lactams could have significant clinical implications.

The aim of this project is to utilize an Mtb mutant that is hypersusceptible to beta-lactams to (i) provide proof of concept that beta-lactams can be effective against Mtb in a mouse model, (ii) identify compounds that inhibit growth of intracellular Mtb by targeting proteins required for resistance to beta-lactams and (iii) identify compounds that could synergize with beta-lactams.
The proposed duration of the project is 24 months and will involve a close collaboration between Cornell University and GSK’s Medicines Development Campus at Tres Cantos.