Synergistic effect of chlorogenic acid and caffeic acid with Fosfomycin in growth inhibition of a resistant Listeria monocytogenes strain

Authors: ZHANG, FANGYUAN - Villanova University; ZHAI, TIANHUA - Villanova University; HAIDER, SHOZEB - Villanova University; Liu, Yanhong; HUANG, ZUYI - Villanova University

Submitted to: ACS Omega
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2020
Publication Date: 3/23/2020
Citation: Zhang, F., Zhai, T., Haider, S., Liu, Y., Huang, Z. 2020. Synergistic effect of chlorogenic acid and caffeic acid with Fosfomycin in growth inhibition of a resistant Listeria monocytogenes strain. ACS Omega. 5(13):7537-7544.
DOI: https://doi.org/10.1021/acsomega.0c00352

Interpretive Summary: Listeria monocytogenes is a pathogenic bacterium that causes a foodborne illness called listeriosis. Fosfomycin is one of the therapeutic antibiotics used in the treatment of listeriosis. However, L. monocytogenes can develop resistance to fosfomycin through the FosX protein that degrades fosfomycin, resulting in loss of effectiveness against the pathogen. In this study, a computational-based approach based on protein information from L. monocytogenes was developed to identify inhibitors to the action of FosX. Two phenolic compounds that have the ability to overcome fosfomycin resistance in L. monocytogenes were identified through this approach. Thus, this computational-based approach has the potential to be used to study and develop strategies to control antimicrobial resistance in bacteria such as L. monocytogenes.

Technical Abstract: Listeria monocytogenes, a human foodborne pathogen that causes listeriosis with high-rate mortality, has been reported to be resistant to commonly used antibiotics. New antibiotics or cocktails of existing antibiotics with synergistic compounds are in high demand for treating this multi-drug-resistant pathogen. fosfomycin is one of the novel and promising therapeutic antibiotics for the treatment of listeriosis. However, some L. monocytogenes strains with the FosX gene were recently reported to survive from the fosfomycin treatment. This work aims to identify FosX inhibitors that can revive fosfomycin in treating resistant L. monocytogenes.since structures and activities of the FosX protein in L. monocytogenes have been well studied, we used an integrated computational and experimental approach to identify FosX inhibitors that show synergistic effect with fosfomycin in treating resistant L. monocytogenes. Specifically, automated ligand docking was implemented to perform virtual screening of the Indofine natural-product database and FDA-approved drugs to identify potential inhibitors. An in vitro bacterial growth inhibition test was then utilized to verify the effectiveness of identified compounds combined with fosfomycin in inhibiting the resistant L. monocytogenes strains. Two phenolic acids, i.e., caffeic acid and chlorogenic acid, were predicted as high-affinity FosX inhibitors from the ligand-docking platform. Experiments with these compounds indicated that the cocktail of either caffeic acid (1.5 mg/mL) or chlorogenic acid (3 mg/mL) with fosfomycin (50 mg/L) was able to significantly inhibit the growth of the pathogen. The finding of this work implies that the combination of fosfomycin with either caffeic acid or chlorogenic acid is of potential to be used in the clinical treatment of Listeria infections.