Cudraflavone C from Artocarpus hirsutus as a Promising Inhibitor of Pathogenic, Multidrug-Resistant S. aureus, Persisters, and Biofilms: A New Insight into a Rational Explanation of Traditional Wisdom

Artocarpus hirsutus Lam., or wild jack, a perennial tree of the Western Ghats of peninsular India, serves as a rich source of flavonoids. The indigenous knowledge of this multipurpose flora chronicles the efficient property of its bark as a natural treatment for various skin infections. Herein, we describe a rational explanation of this traditional knowledge via a broader evaluation of inhibitory activity of one of its phytoconstituents, cudraflavone C (Cud C), a prenyl flavone isolated from stem bark against diverse multidrug-resistant Staphylococcus aureus along with decidedly potent synergy combinations with a standard drug, gentamycin, especially against gentamycin-resistant S. aureus NRS 10119. Cud C exhibited equipotent MIC (4 mu g/mL) against a varied array of MDR strains comprising MRSA, VRSA, and VRE and was nontoxic toward eukaryotic cells with a sizable selectivity index (SI 25-50). Cud C displayed concentration-dependent bactericidal activity against planktonic cells, an excellent biofilm disruption property exceeding that of levofloxacin and vancomycin against preformed S. aureus bioffim, and an enhanced capability to kill intracellular S. aureus more potently than vancomycin, thus exemplifying its position as an antibacterial lead candidate. In addition, S. aureus was unable to generate resistance to Cud C even after exposure for more than 40 days, whereas it generated resistance to levofloxacin within similar to 20 days of exposure. Therefore, the naturally occurring prenylflavone Cud C can be accounted for as one of the reasons for the reported antibacterial properties of the bark of A. hirsutus. Taken together, detailed biological studies propose that Cud C can be considered as an effective antibacterial drug candidate against MDR S. aureus, which is fast becoming a significant threat to public health worldwide.

Automated summary

The prenyl flavone Cudraflavone C from the bark of Artocarpus hirsutus exhibits potent antibacterial activity against multidrug-resistant Staphylococcus aureus, especially when used in combination with the standard drug gentamycin. It shows bactericidal activity against a variety of MDR strains, biofilm disruption property, and an enhanced capability to kill intracellular S. aureus, making it a promising antibacterial lead candidate. Moreover, S. aureus does not develop resistance to Cud C even after prolonged exposure, highlighting its potential as an effective antibacterial drug against MDR strains.