Phloretin Attenuates Virulence Both and by Simultaneously Targeting Listeriolysin O and Sortase A.

The critical roles of sortase A (SrtA) and listeriolysin O (LLO) in pathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents against infection. Additionally, the structures of SrtA and LLO are highly conserved among the members of sortase enzyme family and cholesterol dependent toxin family. Here, phloretin, a natural polyphenolic compound derived from apples and pears that has little anti- activity, was identified to simultaneously inhibit LLO expression and neutralize SrtA catalytic activity. Phloretin neutralized SrtA activity by causing a conformational change in the protein's active pocket, which prevented engagement with its substrate. Treatment with phloretin simultaneously reduced invasion into host cells and blocked the escape of vacuole-entrapped into cytoplasm. Further, -infected mice that received phloretin showed lower mortality, decreased bacterial burden and reduced pathological injury. Our results demonstrate that phloretin is a promising anti-infective therapeutic for infections caused by due to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics.