EU Consortium: AnTBiotic
The aim of these projects is to progress anti-tuberculosis drug candidates to clinical proof-of-concept. Our role is to predict optimal dosing regimens in silico, which will then be used by our partners in clinical trials.
Tuberculosis (TB) today rivals HIV/AIDS as the leading cause of death from infectious diseases. The number of TB patients has never been higher and the growing proportion of drug-resistant TB is threatening control strategies both in the developing and developed world, Eastern Europe being a particularly worrying point in case.
The anTBiotic consortium aims to fuel the long-term TB clinical pipeline while immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB.
More specifically, the proposed studies aim to:
Establish the proof of concept of anti-TB efficacy in humans of a pioneering, first-in-class, low-dose GSK oxaborole clinical drug candidate;
Identify a combination of β-lactam antibiotics suitable for the treatment of MDR TB orally or as a once daily intravenous or intramuscular application; and
Incorporate the best β-lactam combination into an explorative salvage regimen for untreatable patients with extensively drug-resistant TB.
The anti-TB activity in humans will be established in a two-week EBA clinical studies that combine established (CFU, TTP) and new clinical markers (biomarkers, PET/CT).
These datasets will help ascertain anti-TB efficacy in humans and generate confidence on their validity in longer-term drug combination trials. A variety of modelling approaches to predict optimal dosing will be used.
Finally, we intend to use at least one of these novel anti-TB entities as part of a pioneering, non-controlled clinical trial in highly drug resistant subjects in Europe and South Africa. This final clinical intervention will hopefully be of immediate benefit to drug-resistant patients in the EU and elsewhere in addition to generating a strong precedent for further adoption worldwide.
David Barros, Spain
Clif Barry, South Africa/USA
Andreas Diacon, South Africa
Christoph Lange, Germany
JPI-AMR Consortium: "Collateral damage"
Urgent action is required to stem the “apocalyptic” spread of antimicrobial resistance (AMR). However, because the pace of novel drug development lags behind the evolution of novel AMR determinants, new strategies of containment are required. In this multidisciplinary project we develop a resistance-reversal strategy based on the concept of collateral sensitivity (CS). CS between a pair of antibiotics occurs when a mutation causing resistance to one antibiotic potentiates susceptibility to another. By exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies in the community and slow their transmission. The broad aim in this project is to realize the unique promise of CS-informed therapies. To do so, our work packages integrate theoretical biology, evolutionary and molecular microbiology, and in vivo modelling with a specific focus on arresting the transmission of resistant Escherichia coli and Streptococcus pneumoniae.
Combining theory and experiments, we will: 1) test the generality of CS across hundreds of clinical strains of E. coli, and S. pneumoniae; 2) quantify how horizontal transmission of antimicrobial resistance determinants modify CS-networks; 3) identify the underlying molecular mechanisms of CS; and 4) determine the conditions under which CS mediated reversals of resistance occur in vivo.
The expected outcomes of the project are to provide pre-clinical recommendations for therapy to reduce the emergence and transmission of these two globally important bacterial pathogens and to provide a framework to develop CS-based strategies for other bacterial threats.
Pål Johnsen, Norway
Dan Andersson, Sweden
Niels Frimodt-Møller, Denmark
Daniel Rozen, Netherlands