Developing the Natural Prenylflavone Artocarpin from Artocarpus hirsutus as a Potential Lead Targeting Pathogenic, Multidrug-Resistant Staphylococcus aureus, Persisters and Biofilms with No Detectable Resistance

The genus Artocarpus, a nutraceutical, is widely used in traditional medicine for treatment of many chronic diseases including infections. Artocarpus hirsutus Lam., an evergreen tree endogenous to the Western Ghats of India, is a well-documented medicinal plant in Hortus Malabaricus, the oldest comprehensive printed book on the natural plant wealth of Asia. Herein we describe artocarpin, a major isoprenyl flavonoid isolated from the stem bark of A. hirsutus Lam., as the explanation behind the indigenous knowledge reported for treatment of various skin ailments. Artocarpin, a noncytotoxic, isoprenyl flavonoid, is rapidly bactericidal against multiple World Health Organization (WHO) priority 2 pathogens including multidrug-resistant Staphylococcus aureus and Enterococcus sp. with an extended postantibiotic effect. Artocarpin (AH-5) synergizes with gentamicin and linezolid, inhibits bacteria in different physiological states, including under biofilm and in macrophages, and does not induce resistance in S. aureus despite repeated exposure. Artocarpin induces rapid cellular lysis, as confirmed by fluorescence microscopy and scanning electron microscopy analysis as well as by measuring the significantly increased extracellular and concomitantly decreased intracellular adenosine triphosphate levels. When tested in vivo, AH-5 is almost as effective as vancomycin in reducing bacterial load in murine thigh and skin infection models, which is comparable to standard of care (SoC) antibiotics. This is highly significant since AH-5 is a direct natural entity that has been evaluated without any pharmaceutical modification and expresses robust in vitro and in vivo antibacterial activity, which is comparable to highly optimized SoC comparators and further could be considered as an effective clinical, antibacterial drug lead.