Betalactam antibiotics as an untapped potential for TB treatment

In the search for new treatment options for multidrug-resistant tuberculosis (MDR-TB), we will perform the first human drug trial testing oral β-lactam drugs against active TB.

Moreover, we will explore resistance mechanisms of Mycobacterium tuberculosis (Mtb) for β-lactams through in-depth studies of genomics and transcriptomics.In a randomized controlled trial in Australia, the BLAST trial, we will study the early bactericidal activity of cephalexin combined with amoxicillin-clavulanate, in comparison to standard treatment in patients (n=30) with active pulmonary tuberculosis during the first 2 weeks of treatment.

The fall in bacterial sputum load is the primary outcome.

The choice of study drugs was informed by previous in vitro studies by our team.In BetaResist, we will generate resistant Mtb mutants for key β-lactam antibiotics and perform genomic and transcriptomic analysis by whole genome sequencing and RNA-sequencing, respectively. Cell-wall synthesis and efflux pumps are of particular interest for the analysis.

Transcriptomic studies have not previously been done for M.tuberculosis regarding key β-lactams.The 4-year project may potentially lead to a new, safe and oral treatment alternative for MDR-TB, opening up the repurposing β-lactam antibiotics for TB.

BetaResist will provide in-depth knowledge of the expression of Mtb genes involved in β-lactam resistance and may facilitate identifying and mitigating drug resistance of Mtb.