Old war, new battle, new fighters!

Since the discovery of penicillin, antibiotics have been of critical importance in the control of infectious diseases. However, the extensive use and misuse of antibiotics during recent decades led to the widespread development and distribution of resistance to multiple drugs among bacteria. With the alarming levels of antibiotic resistance and the difficulties associated with discovering novel antibiotics, researchers are now investigating alternatives to treat infectious diseases. In contrast to traditional strategies, which aim to kill bacteria or prevent their growth, these new approaches intend to block the ability of bacteria to harm the host by directly inhibiting bacterial virulence factors and are thought to use less selective pressures that limit the development of bacterial resistance. These emerging strategies benefit from the detailed knowledge of the functional and molecular mechanisms underlying key pathogenic determinants acquired during the last decades of research in host-pathogen interactions [1]. Bacterial toxins in particular are primary targets for these novel antivirulence strategies. In this issue of The Journal of Infectious Diseases, Wang et al show that fisetin, a natural flavonoid with negligible antimicrobial activity, has effective antivirulence activity against Listeria monocytogenes by directly interfering with a secreted bacterial toxin. Listeria monocytogenes is a facultative intracellular human foodborne pathogen that causes gastroenteritis, meningitis, encephalitis, and maternofetal infections. Listeriosis is the most frequent cause of death from consumption of contaminated food in Europe and has the third highest cost of illness and loss of quality of life among foodborne infections [2, 3]. Listeria monocytogenes enters the host via the ingestion of contaminated foods, invades the intestine, translocates to mesenteric lymph nodes, and spreads to the liver, spleen, brain, and placenta. During infection, L. monocytogenes has the ability to cross the intestinal, blood-brain, and placental barriers, entering, surviving, and multiplying inside phagocytic and nonphagocytic cells [4]. To establish and sustain infection, L. monocytogenes uses an arsenal of virulence factors to hijack host-signaling pathways [5, 6]. While remaining a real public health concern, L. monocytogenes has emerged as an exceptional model to address the different facets of host-pathogen interactions and the design of new therapeutic strategies. Listeriolysin O (LLO) is a crucial virulence factor produced by L. monocytogenes [7]. It is a pore-forming toxin member of the cholesterol-dependent cytolysin family [8]. LLOmonomers are secreted by the bacteria and oligomerize into a ring at the surface of target cell [9].Membrane insertion of LLO results in ion fluxes across damaged membranes and ultimately leads to cell lysis in conditions of extensive damage and/or inefficient membrane repair mechanisms [10]. Inactivation of LLO results in the inability of L. monocytogenes to escape from the internalization vacuole, thereby decreasing the virulence potential of L. monocytogenes [11, 12]. Besides membrane lysis, it has become apparent that LLO acting from the intracellular or extracellular milieu exerts additional effects on the host cell [7]. Intracellular LLO affects host cell signaling [13, 14], induces autophagy [15], and suppresses reactive oxygen species [16]. LLO was also shown to deregulate host SUMOylation [17], to induce endoplasmic reticulum stress [18] and mitochondrial fragmentation [19], and to promote regulatory epigenetic changes [20]. A previous study showed that subinhibitory concentrations of plant essential oils could inhibit LLO activity and decrease L. monocytogenes virulence, but the specific compound responsible for this effect remained unknown [21]. Wang et al now report the discovery of the natural flavonoid fisetin as an effective antivirulence agent against LLO activity. They showed that fisetin inhibits Received and accepted 11 September 2014; electronically published 17 September 2014. Correspondence: Didier Cabanes, PhD, Institute for Molecular and Cell Biology, Group of Molecular Microbiology, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal ([email protected]. pt). The Journal of Infectious Diseases 2015;211:1361–3 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu521