Comparative proteomic and phosphoproteomic analysis of Mycobacteria treated with flavonoid quercetin and non-flavonoid caffeic acid

Tuberculosis is becoming one of the major health concerns worldwide. Although combinatorial therapy with various anti-tuberculosis drugs is a promising treatment option, increasing drug resistance and co-infections is prompting us to develop new medications or explore anti-mycobacterial compounds from bioactive natural products. Previous studies have proved that various natural compounds, especially polyphenols have anti-mycobacterial activities. However, the detailed molecular mechanism remains unknown. In our study, we utilized the quantitative proteomic strategy to explore the dynamic changes at proteome and phosphoproteome levels with the treatment of flavonoid quercetin and non-flavonoid caffeic acid by using the non-pathogenic model organism M. smegmatis as a model. These two polyphenols are abundant compounds in nature with potential therapeutic effects on infectious diseases. Both polyphenols induced protein changes in the metabolic process of macromolecules and organic compounds. Meantime, quercetin treatment may cause changes in methyltransferase activity and nucleic acid binding. In addition, a reduction in phosphorylation level was observed in several mycobacterial serine/threonine-protein kinases in response to quercetin treatment. In conclusion, our study uncovered the potential antimycobacterial mechanisms of polyphenols, providing new insights into therapeutic strategy in this infectious disease. • Dynamic characterizations of global proteomic changes on mycobacteria treated with polyphenol quercetin and caffeic acid. • Treatment of polyphenols affects mycobacterial transcriptional regulators and virulence factors at proteome level. • Disturbance of mycobacterial protein kinases at phosphorylation level after quercetin intervention.