Abstract
The critical roles of sortase A (SrtA) and listeriolysin O (LLO) in Listeria monocytogenes pathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents against L. monocytogenes 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-L. monocytogenes 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 L. monocytogenes invasion into host cells and blocked the escape of vacuole-entrapped L. monocytogenes into cytoplasm. Further, L. monocytogenes-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 L. monocytogenes due to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics.
Highlights
Listeria monocytogenes, a Gram-positive, opportunistic bacterial species, is a common foodborne intracellular pathogen and the etiological agent of listeriosis, an infection characterized by gastroenteritis, septicemia, meningitis and miscarriage in humans and animals (Dussurget et al, 2004; Posfay-Barbe and Wald, 2009)
Phloretin showed little anti-microbial activity against L. monocytogenes, with a minimal inhibitory concentration (MIC) of 933.44 μM, which is 16-fold higher than the concentration used for the sortase A (SrtA) activity inhibition assay and hemolytic activity analysis
The growth of L. monocytogenes was not apparently affected following treatment with phloretin at the concentrations required for sufficient inhibition of listeriolysin O (LLO) expression and SrtA catalytic activity (Figure 2B)
Summary
A Gram-positive, opportunistic bacterial species, is a common foodborne intracellular pathogen and the etiological agent of listeriosis, an infection characterized by gastroenteritis, septicemia, meningitis and miscarriage in humans and animals (Dussurget et al, 2004; Posfay-Barbe and Wald, 2009). L. monocytogenes can penetrate the host intestinal barrier by invading the intestinal epithelium cells, after which it can multiply within the liver and Inhibition of L. monocytogenes Infection spleen, cross the fetal-placental barrier if present, and penetrate the blood-brain barrier (Cossart, 2011). These critical processes are closely associated with virulence factors for L. monocytogenes, suggesting that targeting these factors could serve as an alternative therapeutic strategy for bacterial infection (Dussurget et al, 2004). This approach would preserve the host’s endogenous microbiome and expand the repertoire of bacterial targets (Clatworthy et al, 2007)
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