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Beta-lactams for Tuberculosis Treatment

Periodic Reporting for period 1 - BLMs 4 TB (Beta-lactams for Tuberculosis Treatment)

Reporting period: 2018-04-01 to 2020-03-31

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.
Actions were structured in six main blocks: (i) In vitro synergy screens to define optimal combinations including beta-lactams; (ii) Microscopy studies at the single cell level to discern antibacterial effects of the beta-lactams alone and in combination; (iii) Mathematical modeling of beta-lactam anti-mycobacterial action; (iv) Transcriptional studies to understand the underlying molecular mechanisms explaining the synergistic interaction of rifampicin with beta-lactams; (v) Management, dissemination and communication activities of the project through manuscripts, press articles, and conference presentations; (vi) Finally, although not initially planned, efforts were also devoted to explore the potential use of BLMs in the treatment of the neglected disease Buruli ulcer.
The project has yielded important results that might help the development of novel anti-TB therapies that include a BLM. They remain highly relevant and we envision a strong potential to directly impact policy-making to adopt official recommendations for the rational use of BLMs for TB and BU treatment.

Main results include: first, a new oral beta-lactam with strong clinical potential has been identified and it is currently progressing to Phase II clinical trials; second, new combinations including BLMs have been identified using a novel in vitro combination assays based on the bactericidal activity of the compounds, instead of typically used growth inhibition assays. These combinations have the potential to inform the use of BLMs in future TB drug therapy clinical trials; third, we have provided insights into the molecular mechanisms of BLM synergy with other partners. This information can further help the understanding of how best and when combine BLMs for TB therapy, and; finally, we identified a novel treatment shortening therapy for Buruli ulcer disease (caused by Mycobacterium ulcerans) that includes a BLMs. This therapy is currently being taken into Phase II clinical trials.

Some of these findings have already been published:

1. The FICI paradigm: Correcting flaws in antimicrobial in vitro synergy screens at their inception. Gómara M, Ramón-García S. 2019. Biochem Pharmacol. 163:299-307. doi: 10.1016/j.bcp.2019.03.001.
2. Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening. Arenaz-Callao MP, et al. 2019. PLoS Negl Trop Dis. 28;13(1):e0007126. doi: 10.1371/journal.pntd.0007126.

and we are currently preparing three more publications. Several presentations and different international conferences were planned, however, the COVID-19 situation forced their cancelation. We have submitted an abstract presentation for some of these results at the virtual TBScience 2020 of The 51th Union World Conference on Lung Health.
We have accomplished several goals that are beyond current state of the art. We have addressed the synergistic interaction of rifampicin and several beta-lactams from a molecular perspective and have identified underlying molecular determinants explaining this interaction, something never reported to date. In addition, we have developed a new technology that allows the analysis of drug combinations in vitro in a more dynamic way than standard currently used assays. This new technology, named OPTIKA (Optimized Time Kill Assays), has the potential to revolutionize the way new regimens for TB therapy are screened and evaluated at the in vitro level. Finally, we have translated this knowledge to propose a new therapy for Buruli ulcer (BU), a disease difficult to manage in rural areas of Africa. Our findings might improve the life of patients afflicted by this very much-neglected disease by reducing a lengthy 8-week treatment by a shorter 4-week therapy.
Conceptual screening process to identify beta-lactam containing synergistic combinations