Principal Investigator (PI)
The Foundation is providing £139,032 in support.
Dr. Kaj Kreutzfeldt
GSK provides 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.
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.