Title:C-Met Inhibitors are Potential Novel Therapeutic Agents Against Listeria monocytogenes Infection Through Blocking the Bacteria Entry into Nonphagocytic Cells
VOLUME: 17 ISSUE: 3
Author(s):Santhosh Puthiyakunnon, Xiaolong He, Swapna Boddu, Sheng-He Huang and Hong Cao
Affiliation:Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515,China.
Keywords:c-Met, Geldanamycin, HGF/SF, InlB, Intracellular infection, Listeria monocytogenes, Tanespimycin.
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.
