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 μg/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 biofilm, 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 ∼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.