Targeting Tuberculosis

Although entering a new era of innovative and personalized medicine in industrialized countries, we still rely on drugs developed more than 50 years ago to treat neglected diseases, such as tuberculosis (TB). Since then, only two new drugs, Sirturo (bedaquiline) and Deltyba (delamanid), have been approved for treating TB. Because they are not known to be more effective than traditional frontline TB antibiotics, they are only used to treat multidrug or extensively drug-resistant cases, which sometimes are incurable. In recent years, governments and pharmaceutical companies are recognizing an urgent need to improve current TB treatments.

In addition to the well-recognized challenges of drug development, TB antibiotic development is particularly limited for a number of reasons, including:

• The causative agent of TB, Mycobacterium tuberculosis, is intrinsically resistant to most available antibiotics.
• TB is an airborne infectious disease that requires research facilities equipped with expensive, biosafety level 3 infrastructure, as well as dedicated, trained personnel.
• TB mainly affects developing countries lacking resources and infrastructure. It was not until recently that major US-based organizations invested in basic and applied TB research. Unfortunately, the European Union neglected TB funding in its Horizon 2020 program.
• The current reward system for drug development is based on company profits from blockbuster drugs that are developed to treat chronic diseases in the industrialized world. Antimicrobials, in general, are not a good business investment under this model because treatment typically involves inexpensive drugs for just a few days or weeks – and in the case of TB and other neglected diseases, the cost of treatment must be minimal.
• There are only a handful of pharmaceutical companies with TB research in their current portfolio – many others have discontinued TB projects over the past decade.

In view of these challenges, new innovative approaches need to be introduced to quickly deliver new effective therapeutics to patients in need. To minimize the cost of developing new treatments for TB, we combined two innovative concepts: drug repurposing and synergy. These concepts for treating TB originated more than ten years ago in the laboratory of one of the authors – Charles Thompson, at the University of British Columbia, Canada. Santiago Ramón-García joined him there in 2007 as a postdoctoral fellow to start the drug discovery program, searching for inhibitors of mycobacterial proteins that confer intrinsic antibiotic resistance. In 2011, we demonstrated that antibiotics with no significant activity against M. tuberculosis could be repurposed for TB therapy if administered in synergistic combinations (1). A screen of a library of FDA-approved drugs, including around 150 antibiotics, identified lead compounds that increased the activity of an antibiotic (spectinomycin) that M. tuberculosis was able to resist. This led to the realization that available drugs, especially antibiotics, commonly act in synergy with one another against M. tuberculosis.  In some cases, compounds used for other therapies also had their own inhibitory activities against M. tuberculosis. Recently, we also reported in vitro activity of cephalosporins alone and in combination with other antibiotics (2).

After a long period of screening, discovery, characterization, and development, we received funding from the Tres Cantos Open Lab Foundation to further develop this program. Santiago worked for two years in Spain at the GlaxoSmithKline (GSK) screening facilities with a focus on repurposing beta-lactams (and in particular cephalosporins) for TB therapy. Our observation showing that first-generation cephalosporins were active against M. tuberculosis was remarkable because they have been available for over 50 years – but no one previously noted their potential against TB. There is now a vast space to explore, including investigations of other beta-lactam families (a recent clinical trial led by GSK validated the potential of beta-lactams for clinical use [3]) and a vision: to translate in vitro activities of cephalosporins into clinical efficacy.

Cephalosporins could be effective antibiotics; however a single drug will be insufficient to control TB, especially in the long term, and we need to continue to fill the development pipeline. Clearly, more funding and commitment from all stakeholders (including funding agencies, governments, academics and the industrial sectors) are needed if we are to reach the WHO’s goal of TB elimination. To this end, it is imperative to foster public-private partnerships such as the TB Drug Accelerator (TBDA) initiative, a groundbreaking partnership between pharmaceutical companies, research institutions, and the TB Alliance.

Given that drug development is a long and expensive process, repurposing old drugs for neglected diseases is a promising avenue. However, this area is neither sufficiently profitable to attract companies nor appealing to academic scientists supported by research grants that rely on publication and short term public disclosure. We believe more efforts and funding should be dedicated to this largely ignored and unexplored avenue, not only for TB, but also for other neglected diseases.