Search for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: an open drug discovery approach
Daire Cantillon, Aaron Goff, Stuart Taylor, Emad Salehi, Katy Fidler, Simon Stoneham and Simon J Waddell
Background: Mycobacterium chimaera is a slowly growing nontuberculous mycobacterium (NTM) associated with outbreaks of fatal infections in patients after cardiac surgery. It is increasingly detected in patients with chronic lung conditions, and causes disseminated disease, osteomyelitis, and chronic skin or soft-tissue infections. We aimed to find new inhibitory compounds and drug repurposing opportunities for this rarely studied mycobacterium, where current therapeutic options often result in poor outcomes.
Methods: In an open drug discovery approach, we screened the Medicines for Malaria Venture Pathogen Box library of 400 drug-like molecules for activity against M.chimaera (NCTC13781) in comparison to the slowly- and rapidly-growing pathogenic mycobacteria, M.tuberculosis and M.abscessus reference strains respectively. Hits from the initial resazurin microtitre cell viability assay (REMA) screen were further characterised by determining the Minimum Inhibitory Concentrations (MICs) and time kill kinetics alongside a panel of drugs commonly used to treat NTM or tuberculosis.
Findings: M.chimaera was inhibited by 21 Pathogen Box compounds. Ten compounds were active against all three mycobacteria. MMV675968, with activity against slowly-growing mycobacteria that likely targets folate metabolism, had an MIC of 2.22 �M (0.8 �g/mL) against M.chimaera. Antimicrobial susceptibility testing also revealed that the oxazolidinones were active against M.chimaera (linezolid MIC 3.13 �g/mL), and that bedaquiline was the most potent compound (MIC 0.02 �g/mL). Doxycycline, a broad-spectrum antimicrobial drug with excellent tissue penetration properties, also inhibited M.chimaera with an MIC of 6.25 �g/mL.
Interpretation: Molecular diagnostics present an opportunity for more effective targeted drug therapies, treating bacterial infections at the species level. We have identified compounds that inhibit the newly-recognised pathogen M.chimaera using an open drug discovery platform. Where the evidence base is poor and the option for expensive drug discovery improbable, we have also found options for drug repurposing. Future in vivo efficacy studies will reveal whether these findings result in new targeted treatment regimens for M.chimaera.