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Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance

This article has been updated

Key Points

  • Antibiotics are losing efficacy in treating many bacterial diseases owing to increasing drug resistance. Meanwhile, antibiotic development has lagged; the last new antibiotic class was introduced in 2003.

  • Antivirulence is an alternative approach that focuses on interfering with bacterial virulence factors instead of central growth pathways to treat disease.

  • Antivirulence drugs have been approved by the US Food and Drug Administration for bacterial toxin-mediated diseases, and investigational drugs for antibiotic-resistant bacteria have entered clinical trials. Several others are in preclinical development.

  • Antivirulence drugs are likely to have distinct properties from those of antibiotics, including reduced selection pressure (meaning they are less likely to lead to drug resistance) and minimal perturbation of the healthy microbiota.

  • However, antivirulence strategies pose unique challenges for drug development and clinical use, and such drugs may need to be used in combinations or as adjuncts to antibiotics.

  • Increased investment and effort are needed to develop new virulence inhibitors and advance existing ones through the translational pipeline.

Abstract

The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways — the target of traditional antibiotics — intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner. Notably, development of antivirulence drugs requires an in-depth understanding of the roles that diverse virulence factors have in disease processes. In this Review, we outline the theory behind antivirulence strategies and provide examples of bacterial features that can be targeted by antivirulence approaches. Furthermore, we discuss the recent successes and failures of this paradigm, and new developments that are in the pipeline.

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Figure 1: The rise of antivirulence approaches.
Figure 2: Antivirulence agents targeting secreted and surface-exposed virulence factors.
Figure 3: Quorum sensing and inhibition in model Gram-positive and Gram-negative pathogens.

Change history

  • 05 May 2017

    In Figure 2, mouse αEbpA serum was incorrectly shown to contain an scFv region. The italicization of bacterial species and genes was also incorrect in some places. These have now been corrected in the online versions of the article.

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Acknowledgements

The authors are supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases and the Postdoctoral Research Associate Program of the US National Institute of General Medical Sciences, US National Institutes of Health, Bethesda, Maryland, USA.

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Glossary

Horizontal gene transfer

The exchange of genetic information between organisms in a manner other than by traditional reproduction. Horizontal gene transfer is a key mechanism for the evolution of antibiotic resistance in bacteria.

Virulence factors

A broad term used to define molecules produced by pathogens that promote disease or damage the host. They include, but are not limited to, adhesins, regulators, toxins and siderophores.

Microbiota

Collective term for all microflora that are found residing in a given environment. Many microorganisms are considered to be part of the beneficial microbiota on human skin and gut.

Bacterial toxins

A diverse variety of molecules that are produced by many pathogenic bacteria and cause injury to cells. Toxins may directly form pores in eukaryotic membranes or transfer enzymes that deregulate essential intracellular pathways or induce cell death. In addition, some toxins modulate immune cell function to thwart immune responses and facilitate immune evasion for the invading pathogens.

Empiric therapy

The use of broad-spectrum antimicrobial therapy before a definitive diagnosis of the disease-causing organism.

Adhesins

Cell-surface components or appendages of bacteria that facilitate adhesion to other cells or to surfaces: for example, fimbriae (pili). Adhesins contribute to host specificity and tissue tropism.

Siderophores

Low-molecular-weight, high-affinity metal chelating agents produced by microorganisms under low-nutrient conditions. Bacteria depend on siderophores to acquire iron in vertebrate hosts so they can replicate and cause disease.

Biofilm

A surface-attached agglomeration of microorganisms embedded in an extracellular matrix. Biofilm-associated infections are difficult to eradicate and are an important reservoir for disseminating and recurring serious infections.

Quorum sensing

A phenomenon describing the regulation of gene expression in response to cell population density and the production and secretion of signalling molecules (auto-inducers) by quorum-sensing bacteria. Effector functions of quorum sensing include the regulation of genes involved in virulence and biofilm formation.

Fab and F(ab′)2

The antigen-binding fragment of an immunoglobulin G antibody after proteolytic digestion. Fab and F(ab′)2 are monovalent and divalent, respectively, and are produced under differing digestion conditions.

Monoclonal antibodies

(mAbs). Antibodies produced by a single B cell clone that are specific to one epitope of an antigen.

Polyclonal antibodies

A pool of antibodies from different B cells that recognize multiple epitopes on the same antigen.

Response regulator

One part of a two-component system — comprising a membrane-embedded sensor and the cytoplasmic response regulator — that activates transcription of a specific set of genes in response to certain stimuli.

Type III secretion system

(T3SS). A needle-like apparatus found in Gram-negative bacteria that delivers substrates across the inner and outer bacterial membranes and the eukaryotic membranes to the host membrane or cytosol.

Single-chain variable fragment

(scFv). An antibody derivative in which the variable domains from the heavy and light chains have been fused with a linker. An scFv retains the capability to bind the target antigen.

Pan-drug-resistant

Resistant to all approved antimicrobial agents with activity against a specific bacterial species.

Type VII secretion system

A specialized secretion system found in Gram-positive bacteria, the most studied of which are in Mycobacterium tuberculosis. Protein substrates are first exported across the inner membrane by an ATP-dependent multimeric protein complex. Secreted substrates can localize to the culture supernatant or remain embedded in the highly hydrophobic mycobacterial cell envelope. Homologous systems are found in other bacteria from the phyla Actinobacteria and Firmicutes.

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Dickey, S., Cheung, G. & Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov 16, 457–471 (2017). https://doi.org/10.1038/nrd.2017.23

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