Screening of the Medicines for Malaria Venture Pandemic Response Box for Discovery of Antivirulent Drug against Pseudomonas aeruginosa

Abstract

The rise of drug-resistant pathogens as well as overuse and misuse of antibiotics threatens modern medicine as the number of effective antimicrobial drugs steadily decreases. Given the nature of antimicrobial resistance development under intense selective pressure such as the one posed by pathogen-eliminating antibiotics, new treatment options which could slow down the emergence of resistance are urgently needed. Resistance development and exhaustion of the arsenal of existing antibacterial agents urgently require an alternative approach toward drug discovery. Herein, we report the screening of Medicines for Malaria Venture (MMV) Pandemic Response Box (PRB) through a cascade developed to streamline the potential compounds with antivirulent properties to combat an opportunistic pathogen, Pseudomonas aeruginosa . To find an agent suppressing the production of P. aeruginosa virulence factors, we assessed the potential of the compounds in PRB with quorum sensing inhibitory activity. Our approach led us to identify four compounds with significant inhibition of extracellular virulence factor production and biofilm formation. This provides an opportunity to expand and redirect the application of these data sets toward the development of a drug with unexplored target-based activity. IMPORTANCE The rise of drug-resistant pathogens as well as overuse and misuse of antibiotics threatens modern medicine as the number of effective antimicrobial drugs steadily decreases. Given the nature of antimicrobial resistance development under intense selective pressure such as the one posed by pathogen-eliminating antibiotics, new treatment options which could slow down the emergence of resistance are urgently needed. Antivirulence therapy aims at suppressing a pathogen’s ability to cause disease rather than eliminating it, generating significantly lower selective pressure. Quorum sensing inhibitors are thought to be able to downregulate the production of virulence factors, allowing for smaller amounts of antimicrobials to be used and thus preventing the emergence of resistance. The PRB constitutes an unprecedented opportunity to repurpose new as well as known compounds with cytotoxicity and in vitro absorption, distribution, metabolism and excretion (ADME) profile available, thus shortening the time between compound discovery and medicinal use.