Small Molecules That Sabotage Bacterial Virulence

doi:10.1016/j.tips.2017.01.004

Trends in Pharmacological Sciences

Volume 38, Issue 4, April 2017, Pages 339-362

https://doi.org/10.1016/j.tips.2017.01.004 Get rights and content

Trends

The evolution and spread of antibiotic-resistant microbes represents a major threat to global health. Combating antibiotic resistance will require new strategies for treating infectious diseases, including the development of new antibiotics and drug targets.

An antivirulence therapy is a compound that targets a virulence pathway required for microbial pathogenesis in the host, but that is not for essential growth in standard in vitro growth conditions.

Experimental antivirulence compounds have been developed that target distinct virulence mechanisms in bacteria, including two-component regulatory systems, adherence, toxins, specialized secretion systems, metabolism, and quorum sensing.

Antivirulence therapies may have advantages over traditional antibiotics because these compounds target factors specific for pathogenesis, potentially reducing selection for resistance and killing of the resident microbiota.

The development of antivirulence strategies enables the translation of basic microbial pathogenesis research into new treatments for infectious diseases.

The continued rise of antibiotic-resistant bacterial infections has motivated alternative strategies for target discovery and treatment of infections. Antivirulence therapies function through inhibition of in vivo required virulence factors to disarm the pathogen instead of directly targeting viability or growth. This approach to treating bacteria-mediated diseases may have advantages over traditional antibiotics because it targets factors specific for pathogenesis, potentially reducing selection for resistance and limiting collateral damage to the resident microbiota. This review examines vulnerable molecular mechanisms used by bacteria to cause disease and the antivirulence compounds that sabotage these virulence pathways. By expanding the study of antimicrobial targets beyond those that are essential for growth, antivirulence strategies offer new and innovative opportunities to combat infectious diseases.

Section snippets

Expanding the Search for New Antibiotic Targets

The evolution and spread of drug-resistant bacterial infections is an urgent threat to our ability to control infectious diseases 1, 2. Antibiotic-resistant infections are associated with increased mortality and are estimated to cause at least 2 000 000 illnesses annually in the USA, and approximately 23 000 deaths [3]. In addition, drug-resistant illnesses are expensive to treat and often require extended time in the hospital, and thus pose additional risks for acquiring secondary infections

Two-Component Regulatory Systems

Bacteria must sense environmental cues and coordinate adaptive responses to changes in the environment to be able to survive in the host. A common sensing and response mechanism in bacteria is the two-component regulatory system (TCS) [29]. A prototypical TCS is composed of a sensor histidine kinase (HK) and a response regulator (RR). The HK is usually located within the bacterial plasma membrane and is responsible for sensing the environmental signal. Once the signal has been sensed, the HK

Bacterial Adherence Mechanisms

Attachment of bacteria to a host surface is often the first step in initiating and establishing an infection. However, the host possesses several mechanisms to prevent and remove bacteria that do not have specialized apparatuses to facilitate attachment, including the coordinated beating of cilia in the nasopharynx, peristaltic motion in the gastrointestinal tract, and the presence of the resident microbiota blocking access of invading bacteria [79]. Further, pathogenic organisms will only

Toxins and Specialized Secretion Mechanisms

Toxin production and delivery to host tissues is essential for several pathogens to promote infection and dissemination. A variety of mechanisms exist to transport toxins and effectors from within the bacterial cytoplasm to the extracellular environment, or, in some cases, toxins are directly injected through host membranes. Secreted toxins can actively disrupt host intracellular signaling cascades, lead to rearrangements of cytoskeletal architecture, loosen tight junctions, and promote the

Metabolic Requirements during Infection

The outcome of a bacterial infection is determined either by the ability of the host to control the infection through immune effectors intended to clear the pathogen or by countermeasures adopted by the invading microbe to subvert them. However, the interplay between the metabolic requirements of the host and the bacterial pathogen is often overlooked [151]. Indeed, minor perturbations to the metabolism of either system during infection can have a significant impact on the outcome in favor of

Concluding Remarks

Antivirulence strategies aim to sabotage pathogen virulence, placing bacteria in a state of increased susceptibility to clearance at the site of infection. One of the theoretical advantages of antivirulence approaches is that, by targeting virulence factors and not directly inhibiting growth, these compounds may exert reduced selective pressure for resistance [15] (see Outstanding Questions). However, bacteria have always evolved resistance to antibiotics, and it stands to reason that

Acknowledgments

Research in the laboratory of R.B.A. is supported by start-up funding from Michigan State University and AgBioResearch, and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (R01AI116605, R21AI105867 and R21AI117018), and Grand Challenges Explorations awards (OPP1059227 and OPP1119065) from the Bill and Melinda Gates Foundation.

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Trends in Pharmacological Sciences

Feature ReviewSmall Molecules That Sabotage Bacterial Virulence

Trends

Section snippets

Expanding the Search for New Antibiotic Targets

Two-Component Regulatory Systems

Bacterial Adherence Mechanisms

Toxins and Specialized Secretion Mechanisms

Metabolic Requirements during Infection

Concluding Remarks

Acknowledgments

Curr. Opin. Pharmacol.

J. Theor. Biol.

Curr. Opin. Microbiol.

Curr. Opin. Microbiol.

Int. J. Med. Microbiol.

Cell Host Microbe

Vaccine

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.​

Cell

Cell Host Microbe

Curr. Opin. Microbiol.

Biochim. Biophys. Acta

Trends Microbiol.

Origins and evolution of antibiotic resistance

Microbiol. Mol. Biol. Rev.

Sampling the antibiotic resistome

Science

Antibiotic Resistance Threats in the United States, 2013

Antimicrobial Resistance Posing Growing Health Threat

Drugs for bad bugs: confronting the challenges of antibacterial discovery

Nat. Rev. Drug Discov.

Common and contrasting themes of plant and animal diseases

Science

Challenges of antibacterial discovery

Clin. Microbiol. Rev.

A brief history of the antibiotic era: lessons learned and challenges for the future

Front. Microbiol.

Chemical biology applied to the study of bacterial pathogens

Infect. Immun.

Anti-virulence strategies to combat bacteria-mediated disease

Nat. Rev. Drug Discov.

The biology and future prospects of antivirulence therapies

Nat. Rev. Microbiol.

Anti-infective strategies of the future: is there room for species-specific antibacterial agents?

Curr. Pharm. Des.

Targeting virulence: can we make evolution-proof drugs?

Nat. Rev. Microbiol.

Gut microbiota in health and disease

Physiol. Rev.

Antibiotic-associated diarrhea: epidemiology, trends and treatment

Future

Genomics of host–pathogen interactions

Prog. Drug Res.

Harnessing the power of the genome in the search for new antibiotics

Science

Using genomics to develop novel antibacterial therapeutics

Crit. Rev. Microbiol.

Genomics in anti-infective drug discovery − getting to endgame

Curr. Pharm. Des.

Insights from genomics into bacterial pathogen populations

PLoS Pathog.

Bugs, drugs and chemical genomics

Nat. Chem. Biol.

Novel genetic techniques and approaches in the microbial genomics era: identification and/or validation of targets for the discovery of new antibacterial agents

Drugs R D

Small-molecule inhibitors of toxT expression in Vibrio cholerae

mBio

Exploiting quorum sensing to confuse bacterial pathogens

Microbiol. Mol. Biol. Rev.

Approaches targeting the type III secretion system to treat or prevent bacterial infections

Expert Opin. Drug Discov.

Biological insights from structures of two-component proteins

Annu. Rev. Microbiol.

Encyclopedia of bacterial gene circuits whose presence or absence correlate with pathogenicity − a large-scale system analysis of decoded bacterial genomes

BMC Genomics

Feature Review
Small Molecules That Sabotage Bacterial Virulence

J. Biol. Chem.