Key Points
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New therapeutic strategies are urgently needed to improve our chances of success in combating infectious diseases. Bacteria, such as Staphylococcus aureus and Enterococcus faecalis, have emerged in the clinic that are resistant to multiple antibiotics and drugs of last resort.
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An attractive approach in the discovery of new therapeutics is to target bacterial virulence — that is, to impair processes that are required for a bacterium to establish an infection and cause disease without placing direct life-or-death pressure on the organism. Targeting virulence in this way would help to preserve the many symbioses between the microorganism and host that contribute to human health, but that are radically disrupted by traditional antibacterial therapy.
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The molecular-level battles between the pathogen and host provide numerous opportunities to impair bacterial progression through an infection cascade (for example, adherence to host cells) and to ameliorate the accompanying consequences to the host (for example, toxin production).
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Some of the most pursued avenues of antivirulence drug-discovery efforts include those that target bacterial adhesion and toxin production and function. Strategies that aim to impair adhesion and toxin action can act early to prevent the assembly of adhesive machinery or toxin expression or secretion. Alternatively, they can act later to block adhesion using receptor mimics or neutralize toxins, for example, by using antibodies.
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Additional targets include quorum-sensing systems and two-component response systems, the complexities of which we appreciate and are beginning to dissect in more detail. These are crucial to the genetic and molecular control of the production of virulence factors that are important to many processes, such as adhesion, motility and biofilm formation.
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In the future, it is imperative that we determine the genetic and molecular bases of bacterial virulence for all organisms and the dynamic exchange during host–pathogen interactions from both the pathogen and host perspectives. New insights are needed to reveal vital genetic or molecular bottlenecks, and to target the 'Achilles' heel' of a pathogen during infection. Ultimately, we may need to combine the strengths of synergistic therapies.
Abstract
The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.
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Acknowledgements
The authors acknowledge funding from the National Institutes of Health to S.J.H. (grant numbers P50-ORWH/DK64540, R01AI029549, R01AI048689 and R01DK51406), G.R.M. (grant number R01GM068460) and L.C. (grant number T32A107172).
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Gary R. Eldridge is President and Chief Executive Officer of Sequoia Sciences, Missouri, USA.
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Glossary
- Riboswitch
-
An mRNA control element that changes conformation in response to the binding of a metabolite (for example, glycine, lysine and coenzyme B12) and influences gene expression.
- Microbiota
-
The entire collection of microorganisms (bacteria, archaea, fungi, sometimes protozoa and viruses) that are resident on or in the host.
- Pilus
-
A non-flagellar filamentous appendage that is formed on the surface of many bacteria.
- Quorum sensing
-
(QS). The process by which bacteria use signalling molecules to monitor bacterial density and coordinate gene expression in a population-density-dependent manner.
- Adhesin
-
The surface-exposed bacterial molecule that mediates specific binding to a receptor or ligand on a target cell.
- Autotransporter
-
A large family of secreted proteins in Gram-negative bacteria that harbour three functional domains — the amino-terminal signal peptide, the secreted mature protein (passenger domain) and a carboxy-terminal translocator domain — to allow secretion of the passenger protein.
- Biofilm
-
A community of cells that are attached to a surface or interface or to each other, and are imbedded in a self-made, protective matrix of extracellular polymeric substances.
- Chaperone–usher system
-
A system that facilitates the folding, transport and ordered assembly of pilus subunits at the cell surface.
- Botulism
-
A rare, but serious illness that is caused by a nerve toxin, botulinum, that is produced by the bacterium Clostridium botulinum.
- Chemical genetics
-
The strategy of using small molecules to alter and interrogate biological processes. The small-molecule tools of dissection in this approach harbour the precious chemical scaffolds that may lead directly to new therapeutics.
- Project BioShield
-
The Project BioShield Act was incorporated into law by the United States government in July 2004. Through Project BioShield, $5.6 billion will be invested by 2013 in the development of new technological and therapeutic countermeasures against potential bioterrorism agents and to purchase and stockpile effective therapeutics to prevent and treat the illnesses that are related to these threats.
- Haemolytic uraemic syndrome
-
A disease that primarily affects infants and children and is characterized by the loss and destruction of red blood cells. Occurs most commonly in children after a gastrointestinal infection or upper respiratory-tract infection and can lead to kidney failure.
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Cegelski, L., Marshall, G., Eldridge, G. et al. The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6, 17–27 (2008). https://doi.org/10.1038/nrmicro1818
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DOI: https://doi.org/10.1038/nrmicro1818
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