Anti-Virulence Strategies to Combat Bacteria-Mediated Disease

REVIEWS Anti-virulence strategies to combat bacteria-mediated disease David A. Rasko* and Vanessa Sperandio‡ Abstract | Antibiotic resistance is one of the greatest challenges of the twenty-first century. However, the increasing understanding of bacterial pathogenesis and intercellular communication has revealed many potential strategies to develop novel drugs to treat bacteria-mediated disease. Interference with bacterial virulence and/or cell-to-cell signalling pathways is an especially compelling approach, as it is thought to apply less selective pressure for the development of bacterial resistance than traditional strategies, which are aimed at killing bacteria or preventing their growth. Here, we discuss the mechanisms of bacterial virulence and present promising anti-virulence strategies and compounds for the future treatment of bacterial infections. Anti-virulence drug Infectious diseases are the leading cause of death world- Consequently, we are now entering the post-antibiotic A drug that targets bacterial wide, with bacterial infections contributing substantially era, with limited treatment options for many bacterial virulence but is not to this high rate of mortality. Although in 1969 the infections, such as the now widely disseminated vanco- bacteriostatic (growth General Surgeon of the United States proclaimed that mycin-resistant Enterococcus species3 and methicillin- inhibiting) or bacteriocidal “We have closed the chapter on infectious diseases, due to resistant Staphylococcus aureus4 (MRSA). Although these (bacteria killing). antibiotics”, many bacteria are now multidrug resistant. two pathogens are by no means the only examples, they There are a wide range of factors that the invading are the most recognizable in the popular literature and bacteria must overcome to cause disease. These include prove that inappropriate and indiscriminate anti biotic innate factors such as pH, temperature and host secre- treatment can lead to resistant organisms in a short tions, as well as active factors such as the immune period of time. However, many alternative strategies are response, which act to prevent bacterial colonization. currently being investigated that are based on the inhibi- In addition to the host factors are the existing bacterial tion of virulence rather than of bacterial growth. Such microbiota that are resident at most anatomical niches strategies might apply a milder evolutionary pressure for in which infection occurs. This resident microbiota the development of resistance as most virulence traits are must be removed or exploited for a successful infection. not essential for bacterial survival. Bacterial pathogens use many diverse strategies to cause Bacteria sense their environment and, once in the disease in human hosts1. host, they respond by initiating a defined programme Traditional approaches to combat bacterial infection to activate virulence traits5,6. Anti-virulence signalling *Department of Microbiology were primarily identified in and derived from other strategies may specifically interfere with the ability and Immunology, Institute for microorganisms. These approaches rely on the disrup- of the bacteria to recognize host signals that alert the Genome Sciences, University of Maryland School of tion of the growth cycle by preventing the synthesis and bacteria that they are at the site of infection and/or acti- Medicine, Baltimore, assembly of key components of bacterial processes such vate specific virulence traits that are needed to establish Maryland 21201, USA. as cell wall synthesis, DNA replication and protein syn- infection. By preventing the expression or activity of ‡Departments of Microbiology thesis2. Although these strategies and compounds were virulence traits, the bacteria are less able to colonize the and Biochemistry, UT Southwestern Medical highly effective, they resulted in substantial stress on the host. In addition, as this strategy does not directly kill Center, Dallas, Texas target bacterium, which rapidly selected for resistant sub- the bacteria, there is presumably less evolutionary pres- 75390-9048, USA. populations3. For example, in a population of ~10 billion sure for the development of resistant clones than with Correspondence to V.S. bacteria, a minute portion will be resistant to a given traditional antibiotics. It is thought that this inhibition e-mail: Vanessa.sperandio@ antibiotic, owing to natural bacterial mutation rates. could allow the host immune system, including the nor- utsouthwestern.edu doi:10.1038/nrd3013 If the majority of the non-resistant cells are killed, the mal microbiota, to prevent bacterial colonization or clear Published online smaller fraction that is resistant may quickly grow and any established infection. In addition, these anti-virulence 18 January 2010 become the dominant proportion of the population. drugs could potentially be used in combination with NATURE REVIEWS | DRUG DISCOVERY VOLUME 9 | FEBRUARY 2010 | 117 © 2010 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Bacterial virulence strategies as AB toxins because they are composed of the active subunit (A subunit) and a multimeric receptor-binding Virulence Organisms that Associated disease subunit (B subunit)13 (FIG. 1). The B subunit adheres strategies use the strategy to a surface-exposed receptor on the eukaryotic cell, Toxin Bacillus anthracis Anthrax infection13 and the A subunit enters the cell, in which it exerts its production Escherichia coli Bloody diarrhoea, haemolytic enzymatic activity. The Shiga toxin B subunit binds to uraemic syndrome, and kidney the globosylceramide 3 (Gb3) ganglioside that is abun- 14 and neurological damage dant on kidney and brain endothelial cells, whereas the Clostridia spp. Gangrene11 A subunit inhibits host protein synthesis by cleaving a Adhesive Almost all pathogens that Many infections18 glycosidic bond on the 28S ribosomal RNA in the 60S 14 mechanisms remain within the host subunit of the ribosome . By contrast, anthrax toxin is a tripartite toxin that has a single binding subunit known Specialized Escherichia coli Gastrointestinal infections14 secretion as the protective antigen (PA) and two active subunits Yersinia spp. Plague and gastrointestinal known as the lethal factor (LF) and the edema factor systems 72 infections (EF). The PA subunit is secreted from the bacterium as Chlamydia trachomatis Urethritis, proctitis (rectal disease an 83 kDa subunit, which binds to the host cell surface. and bleeding) and trachoma69 It is cleaved by a host protease to a 63 kDa subunit that Salmonella spp. Various infections in a wide range can assemble into the heptameric ring in the lysosome of hosts75,76 wall, in which it forms a pore enabling the extrusion of 15 Regulation of All pathogens All infections5,79–81 LF and EF into the host cell cytoplasm . Once secreted virulence genes into the cytoplasm, the LF functions as a metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPKKs), resulting in altered signalling in the host cell. EF is an adenylyl cyclase enzyme that, when activated by established or novel antimicrobials in a synergistic man- calmodulin, dramatically increases the cyclic AMP levels ner to extend the lifespan of these drugs7,8. One recent in the cell. The net effect of EF in human tissue is the promising strategy relies on newly discovered synthetic accumulation of fluid in extracellular spaces16. These are or natural small organic compounds that serve as a only two examples of toxin activities; however, each has generation of novel anti-virulence drugs5,9. a number of steps that could be therapeutically inhibited This Review provides a brief overview of the mecha- (FIG. 1). nisms that bacteria use to cause disease in a host. Promising anti-virulence strategies to overcome these Adhesins and biofilms. To effectively colonize the host mechanisms that are currently under investigation and and promote disease, bacteria must attach to host cells. possible future approaches are discussed. Most bacteria have a specific host range and will only infect hosts that express particular receptors for bacte- Molecular mechanisms of bacterial virulence rial adhesion factors on their cell surface. Furthermore, Bacteria use an array of virulence factors to cause disease once within the host, bacteria will infect only the subset in the human host. These factors include adhesins, which of cells or tissues that express the appropriate receptor. bind to host cells and facilitate colonization; toxins, which The human body has a number of innate responses, kill or change signal transduction in mammalian cells; such as peristaltic motion in the gastrointestinal tract and specialized secretion systems to deliver effectors. and the coordinated beating of cilia in the nasopharyn- Because expression of these virulence traits is metaboli- geal regions, which remove bacteria that do not have cally expensive, gene expression is exquisitely regulated the appropriate adhesive capabilities17. The attachment so that it only occurs at the right site for colonization in of bacteria to a host cell is an intricate process governed the host (TABLE 1). Here, we introduce and review these by the adhesin on the bacteria and the receptor on the mechanisms of bacterial virulence. host cell18 (FIG. 2). Adherence is often only the first step in the infection process, which also involves internaliza- Toxins. Broad arrays of toxins are secreted by bacterial tion, deeper tissue penetration and possible systemic Adhesins species, resulting

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