Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the most deadly infectious disease and one of the top 10 causes of death in the world, ranking above HIV/AIDS. Worldwide, around 10 million people fall ill with tuberculosis (TB) each year. The disease can affect anyone anywhere, but most people who develop TB (about 90%) are adults. Almost 90% of cases each year are in 30 high TB burden countries. Globally, an estimated 1.7 billion people are infected with Mtb and are thus at risk of developing the disease.
TB treatment is lengthy (6 months) with unpleasant side effects. Poor compliance and suboptimal treatment lead to therapy failure (relapse) and increased likelihood of developing drug-resistant forms of the disease (MDR or XDR-TB). Drug-resistant TB continues to be a public health threat. In 2018, there were about half a million new cases of rifampicin-resistant TB (of which 78% had multidrug resistant TB). Patients infected with resistant strains of Mtb must undergo treatments that are even longer (up to 24 months) and associated with severe side effects but, despite this, only 30-50% of patients have positive treatment outcomes. New TB treatments are thus urgently needed to shorten therapy and cure all forms of the disease. However, developing new antimicrobials is a costly and lengthy process and drug repurposing (i.e. identifying new uses for existing drugs) is a timely and cost-effective approach to generate new TB treatments.
Beta-lactams (BLMs) are a family of antibiotics with an exceptional record of clinical safety in humans to treat bacterial infections but have been traditionally regarded as ineffective against Mtb. However, several studies performed by the investigators of this project have demonstrated, first, the clinical efficacy of meropenem combined with clavulanate, second, proposed the cephalosporins (a subset of the BLM family) as potential anti-TB agents and, third, demonstrated that BLMs display strong synergistic interactions with rifampicin, the cornerstone antibiotic in TB therapy. The potential of BLMs for treatment of M(X)DR-TB is now undeniable and their development is one of the best immediate approaches to develop new TB regimens.
The overarching goal of the proposed research was to provide high quality molecular and pharmacodynamic pre-clinical data of selected BLMs alone and in combination to inform future and on going TB clinical trials on the evaluation of BLMs. This goal was structured in two focused questions: (i) which BLMs to use and how to combine them in an optimal BLM-containing TB regime to shorten the duration of TB therapy, prevent relapse and treat M(X)DR-TB and; (ii) understanding the underlying molecular mechanism of the interactions between BLMs and their synergistic partners.
Thanks to this project we have now a clearer view from an in vitro perspective of optimal synergistic companion partners for beta-lactams. Our data suggest that BLMs have a clear potential in the treatment of TB and other mycobacterial diseases in novel combinatorial therapies that could treat MDR/XDR disease or even shorten therapy.
