Principal Investigator (PI)
The Foundation is providing £206,497 in support.
Stefan Prior - Irene Perez - Juan Calvet
The in-kind contributions from GSK will involve:
HTS using the GSK chemical library
Cytotoxicity, solubility, stability, …assays to define the value of identified compounds
Chemistry support for SAR and compound selection
Proteomics approaches
In vivo activity in a mouse model of TB virulence
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have alarmingly spread worldwide and make treatment difficult or even impossible. In addition, the one third of the human population latently infected with TB (LTBI) constitutes an enormous reservoir. Antivirulence therapies with small molecules that sabotage bacterial survival in the host may have advantages over traditional antibiotics because it targets factors required for pathogenesis, potentially reducing selection for resistance and limiting collateral damage to the resident microbiota (1, 2).
Our project proposes a novel approach to disarm M. tuberculosis (Mtb), focused on searching antivirulence therapies against transcription factor PhoP as a paradigm regulon essential for Mtb virulence (3, 4). Recently, a small molecule inhibiting a transcription factor has been described to revert antibiotic resistance (5). We propose the construction of a reporter Mtb strain by placing strongly PhoP-regulated promoters (4) upstream GFP which will allow the screening of the complete GSK compound collection. Loss of GFP fluorescence upon treatment, indicative of selective virulence inhibition, can be easily monitored by high-throughput screening. Potential synergies between inhibitors, or between inhibitors and current anti-TB drugs will be assayed. We will confirm whether these compounds are active in macrophage and mouse models of TB and we also plan to assay the selected compounds against representative isolates of Mtb Complex lineages, which reflect the current genetic diversity of TB worldwide.