Chemical Biology Applied to the Study of Bacterial Pathogens

Anthouard, Rebecca; DiRita, Victor J.

doi:10.1128/iai.02021-14

Cited by 16 publications

(17 citation statements)

References 103 publications

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“…Antivirulence compounds, sometimes referred to as anti-infective compounds, are an alternative approach to traditional therapeutic intervention of bacterial infections that have been actively investigated [9–12]. Antivirulence compounds disarm the pathogen by targeting in vivo required virulence factors as opposed to growth cycle or viability mechanisms.…”

Section: Expanding the Search For New Antibiotic Targetsmentioning

confidence: 99%

“…Anti-infective compounds can limit off-target effects against the resident microbial community by directly targeting a pathogen-specific virulence factor. Together, the increasing understanding of bacterial pathogenesis and sequencing-based approaches have yielded significant insights into the virulence requirements necessary during infection, revealing many potential targets to develop new treatments [9, 18–25]. …”

Section: Expanding the Search For New Antibiotic Targetsmentioning

confidence: 99%

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Small Molecules That Sabotage Bacterial Virulence

Johnson

Abramovitch

2017

Trends in Pharmacological Sciences

105

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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 rather than directly target viability or growth. This approach to treating bacterial-mediated diseases may have advantages over traditional antibiotics as 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, innovative opportunities to combat infectious diseases.

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Section: Expanding the Search For New Antibiotic Targetsmentioning

confidence: 99%

Section: Expanding the Search For New Antibiotic Targetsmentioning

confidence: 99%

Small Molecules That Sabotage Bacterial Virulence

Johnson

Abramovitch

2017

Trends in Pharmacological Sciences

105

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“…10 This has sparked a variety of proposals for alternative antibiotic strategies, including antivirulence strategies. 11 Antivirulence compounds attenuate virulence without directly killing bacteria, and instead prevent processes that are essential for infection such as adhesion to host cells or the production of toxins. The immune system can then clear these emasculated bacteria.…”

Section: Introductionmentioning

confidence: 99%

Not just an antibiotic target: Exploring the role of type I signal peptidase in bacterial virulence

Walsh

Craney

Romesberg

2016

Bioorganic & Medicinal Chemistry

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The looming antibiotic crisis has prompted the development of new strategies towards fighting infection. Traditional antibiotics target bacterial processes essential for viability, whereas proposed antivirulence approaches rely on the inhibition of factors that are required only for the initiation and propagation of infection within a host. Although antivirulence compounds have yet to prove their efficacy in the clinic, bacterial signal peptidase I (SPase) represents an attractive target in that SPase inhibitors exhibit broad-spectrum antibiotic activity, but even at sub-MIC doses also impair the secretion of essential virulence factors. The potential consequences of SPase inhibition on bacterial virulence have not been thoroughly examined, and are explored within this review. In addition, we review growing evidence that SPase has relevant biological functions outside of mediating secretion, and discuss how the inhibition of these functions may be clinically significant.

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“…As with genetic manipulation, these compounds provide investigators with molecular scalpels that can dissect host-pathogen interactions, allowing one to understand the contribution of these interactions to disease in animal models, as well as to identify putative host targets. Indeed, there are a number of examples in which chemical biology through the generation of molecular probes has aided in the study of bacterial pathogenesis (239). Ultimately, continued development of antiadhesive strategies will further our understanding of bacterial virulence as it relates to human disease and provide unique approaches to the treatment of infectious diseases.…”

Section: Concluding Remarks: the Advantages Of Targeting Pathogen Adhmentioning

confidence: 99%

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

2016

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Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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Chemical Biology Applied to the Study of Bacterial Pathogens

Cited by 16 publications

References 103 publications

Small Molecules That Sabotage Bacterial Virulence

Small Molecules That Sabotage Bacterial Virulence

Not just an antibiotic target: Exploring the role of type I signal peptidase in bacterial virulence

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

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