Effects of caspofungin, tolcapone and other FDA-approved medications on MRSA susceptibility to vancomycin

• Published in: Journal of global antimicrobial resistance. Vol. 22; pp. 283 - 289
• Main Authors: Moore, Jonah A., Meakin, Michaela, Earl, Mikaela H., Kummer, Tiffany M., McAleer, Jeremy P., Long, Timothy E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.09.2020; Elsevier
• Subjects: Antibiotics; Caspofungin; Flow cytometry; MRSA; Tolcapone; Vancomycin; Flow cytometry; Vancomycin; Antibiotics; Tolcapone; MRSA; Caspofungin; vancomycin; flow cytometry; tolcapone; antibiotics; caspofungin
• ISSN: 2213-7165; 2213-7173
• DOI: 10.1016/j.jgar.2020.03.014

•Vancomycin (VAN) is a first-line treatment for systemic methicillin-resistant Staphylococcus aureus (MRSA) infections.•Other medications taken during treatment could alter MRSA susceptibility to VAN.•Caspofungin (CAS) and tolcapone (TOL) exhibit synergistic and additive potentials with VAN.•CAS exhibits bactericidal abilities to accelerate MRSA eradication with VAN.•TOL exhibits bacteriostatic abilities to decelerate MRSA eradication by VAN. Vancomycin is a first-line antibiotic for the treatment of invasive infections in humans caused by methicillin-resistant Staphylococcus aureus (MRSA). Based on the premise that antibiotic combinations can exhibit synergistic and antagonistic interactions, medications used for the treatment of infection and other medical conditions were evaluated for their ability to alter MRSA susceptibility to vancomycin. A chemical library comprised of 1237 pharmacological agents was evaluated in a 96-well plate format for its ability to inhibit MRSA growth in combination with half the minimum inhibitory concentration (MIC) of vancomycin. Caspofungin and tolcapone were further assessed for synergistic potential by isobologram (checkerboard) and flow cytometric analysis. In addition, the antibacterial activity spectrum and effects of growth conditions of the two drugs were delineated by MIC determination. The study identified 17 nonantibiotic library members with synergistic or additive potential, including caspofungin and tolcapone. Further analyses revealed that the respective medications for invasive candidiasis and Parkinson disease were bactericidal and bacteriostatic inhibitors of S. aureus growth. Flow cytometric analysis of viability further demonstrated that caspofungin in combination with vancomycin increased MRSA cell death in an additive manner, whereas tolcapone appeared to suppress the bactericidal action of vancomycin. Overall, this proof of concept study concluded that nonantibiotic drugs can alter the pharmacodynamic properties of vancomycin, with potential clinical implications in patients with a MRSA infection receiving medications for other medical conditions.