Development of novel Mycobacterial Tolerance Inhibitors (MTIs) against MDR/XDR tuberculosis

Therapeutics

Research Project: 2019-03-01 - 2023-08-31

Total sum awarded: €1 251 435

In 2017, WHO published the Global Priority Pathogen lists with the aim to promote research and development of new treatments that are effective against microbes resistant to multiple antibiotics. Among them, multi- and extensively drug resistant Mycobacterium tuberculosis caused 48% of new tuberculosis (TB) cases in some countries in 2016. Current regimens for the treatment of TB include a combination of antibiotics developed for their strong efficacy against drug sensitive bacterium. The inadequacies of present TB therapies demand discovery of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered and developed a new family of ring-fused 2-pyridones (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently sensitise Mtb to stresses encountered during infection and restores activity to the frontline antibiotic isoniazid (INH) in otherwise INH-resistant Mtb isolates. Our short-term objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimise the current lead MTIs for translation to a therapeutic, and reveal new insights into pathways of drug tolerance and resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current regimens for patients with drug-resistant TB. We will also generate a deeper understanding of the MTI’s mode of action and their potential in synergistic interactions with other drugs. Importantly, we will also study how likely it will be for Mtb to develop resistance to combinations of MTIs and INH and other antibiotics.

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Fredrik Almqvist, Umeå University, Sweden (Coordinator)
Camille Locht, University of Lille, CNRS, INSERM, France (Partner)
Tone Tønjum, University of Oslo, Norway (Partner)
Jesús Blázquez, Centro Nacional de Biotecnología, Spain (Partner)
Christina Stallings, Washington University School of Medicine, USA (Observer)

In 2017, WHO published the Global Priority Pathogen lists with the aim to promote research and development of new treatments that are effective against microbes resistant to multiple antibiotics. Among them, multi- and extensively drug resistant Mycobacterium tuberculosis caused 48% of new tuberculosis (TB) cases in some countries in 2016. Current regimens for the treatment of TB include a combination of antibiotics developed for their strong efficacy against drug sensitive bacterium. The inadequacies of present TB therapies demand discovery of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered and developed a new family of ring-fused 2-pyridones (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently sensitise Mtb to stresses encountered during infection and restores activity to the frontline antibiotic isoniazid (INH) in otherwise INH-resistant Mtb isolates. Our short-term objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimise the current lead MTIs for translation to a therapeutic and reveal new insights into pathways of drug tolerance and resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current regimens for patients with drug-resistant TB. We will also generate a deeper understanding of the MTI’s mode of action and their potential in synergistic interactions with other drugs. Importantly, we will also study how likely it will be for Mtb to develop resistance to combinations of MTIs and INH and other antibiotics.

Call

2018 - Innovations against antibiotic-resistant bacteria: New targets, compounds and tools