C-Met Inhibitors are Potential Novel Therapeutic Agents Against Listeria monocytogenes Infection Through Blocking the Bacteria Entry into Nonphagocytic Cells

Abstract

High lethality of infections caused by Listeria monocytogenes still remains a major clinical problem in spite of their susceptibility to a wide spectrum of antibiotics. The refractoriness towards treatment is primarily due to its amazing capacity to invade non-phagocytic cells and replicate there in, imparting the dual protection from immune response and antimicrobials. Therefore, generating new anti-infective drugs against intracellular infections has emerged as an urgent issue in the therapeutics of listeriosis. Researches have demonstrated that, internalization of Listeria monocytogenes into nonphagocytic cells is mediated by the interactions between the two bacterial invasion proteins, InlA and InlB, and their cellular surface receptors, E-cadherin and c-Met. As InlB promotes entry into various cell types, such as hepatocytes, epithelial cells and endothelial cells, targeting of InlB-c-Met mediated invasion is important for specifically blocking their intracellular infection. Furthermore, our preliminary in vitro studies have shown that a GA (Geldanamycin, GA) analogue, 17-AAG (tanespimycin) which is widely used in cancer therapy have important therapeutic potential by significantly enhancing the capacity of ampicillin to kill intracellular L. monocytogenes, and to protect the infected HBMECs from the cytocidal effects of this bacterium. We report here, the feasibility of tanespimycin as a potential anti-intracellular infective drug and its clinical relevance in a broader prospective, including the significant advancements in therapeutic approaches, drug effectiveness and toxicity. Exploring the therapeutic effects of c-Met inhibitors such as tanespimycin on L. monocytogenes intracellular infection may provide an alternative novel strategy for the development of antimicrobial agents for treatment of infectious diseases.