Pilicides — Small Molecules Targeting Bacterial Virulence

Aaberg, Veronica; Almqvist, Fredrik

doi:10.1002/chin.200739269

Cited by 7 publications

(10 citation statements)

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“…They act as competitive inhibitors of chaperone‐subunit association, an essential step in pili translocation to the bacterial surface. Similar molecules targeting other adhesion factors, such as curlicides, have also been reported to severely impair curli‐dependent biofilm formation and pathogenesis (Pinkner et al ., ; Aberg & Almqvist, ; Cegelski et al ., ). Attenuation of virulence by acylated hydrazones of salicylaldehydes via inhibition of type III secretion in different strains of Yersinia, Pseudomonas, E. coli , and Chlamydiae has also been demonstrated (Aberg & Almqvist, ).…”

Section: Lessons To Be Learned From Bad‐neighborlinessmentioning

confidence: 99%

“…Similar molecules targeting other adhesion factors, such as curlicides, have also been reported to severely impair curli‐dependent biofilm formation and pathogenesis (Pinkner et al ., ; Aberg & Almqvist, ; Cegelski et al ., ). Attenuation of virulence by acylated hydrazones of salicylaldehydes via inhibition of type III secretion in different strains of Yersinia, Pseudomonas, E. coli , and Chlamydiae has also been demonstrated (Aberg & Almqvist, ). Competitive inhibition for specific bacterial adhesion is a related strategy aimed at inhibiting fimbrial lectins using specific saccharidic ligands competing with cell‐surface‐exposed bona fide fimbriae ligands (Korea et al ., ).…”

Section: Lessons To Be Learned From Bad‐neighborlinessmentioning

confidence: 99%

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Multi-species biofilms: how to avoid unfriendly neighbors

2012

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Multi-species biofilm communities are environments in which complex but ill understood exchanges between bacteria occur. Although monospecies cultures are still widely used in the laboratory, new approaches have been undertaken to study interspecies interactions within mixed communities. This review describes our current understanding of competitive relationships involving nonbiocidal biosurfactants, enzymes, and metabolites produced by bacteria and other microorganisms. These molecules target all steps of biofilm formation, ranging from inhibition of initial adhesion to matrix degradation, jamming of cell-cell communications, and induction of biofilm dispersion. This review presents available data on nonbiocidal molecules and provides a new perspective on competitive interactions within biofilms that could lead to antibiofilm strategies of potential biomedical interest.

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Section: Lessons To Be Learned From Bad‐neighborlinessmentioning

confidence: 99%

Section: Lessons To Be Learned From Bad‐neighborlinessmentioning

confidence: 99%

Multi-species biofilms: how to avoid unfriendly neighbors

2012

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“…They contain the FimH adhesin at their tip, which mediates binding to mannosylated receptors present on the luminal surfaces of mammalian bladder epithelial cells—an event that is critical in the pathogenesis of urinary tract infection16–18. Thus, type 1 pili are essential virulence factors representing an excellent target for therapeutic intervention19.…”

mentioning

confidence: 99%

“…Previously, we discovered that the dihydro thiazolo ring-fused 2-pyridone provides an excellent scaffold for the rational design and synthesis of pilicides (for example, BibC10 ( 1 ), Fig. 1a) that block type 1 pilus biogenesis in E. coli 19,24–26. Type 1 pili are assembled by the well-characterized chaperone-usher pathway27,28.…”

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confidence: 99%

Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation

et al. 2009

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Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type 1 pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1-dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1 pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1 pili endows unique anti-biofilm and anti-virulence activities on these compounds.Bacterial biofilms are complex microbial communities that exhibit reduced sensitivity to conventional antibiotics, host defenses and external stresses 1,2 . Multiple determinants contribute to biofilm development and maintenance, and their requirements in biofilm formation may vary depending on environmental conditions. In addition, factors important in

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“…An alternative approach is to inhibit pilus formation by blocking the activity of chaperone-usher systems necessary for their biogenesis. Pilicides are in development for a number of bacterial species including Escherichia coli [35–38]. Given the key role pili play in initial adhesion and the fact that the chaperone-usher system plays a pivitol role in pili biogenesis for a number of pathogenic species, it is hoped that pilicides may be effective against multiple species, providing a broad-range antibacterial therapeutic option.…”

Section: Introductionmentioning

confidence: 99%

Novel strategies to combat bacterial virulence

Lynch

Wiener-Kronish²

2008

Current Opinion in Critical Care

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Purpose of review-Incidences of antimicrobial resistant infections have increased dramatically over the past several decades and are associated with adverse patient outcomes. Alternative approaches to combat infection are critical, and have led to the development of more specific drugs targeted at particular bacterial virulence systems or essential regulatory pathways. The purpose of this review is to highlight the recent developments in anti-bacterial therapy and the novel approaches toward increasing our therapeutic armory against bacterial infection.Recent findings-Although classic antibiotic development is not occurring rapidly, alternative therapeutics that target specific bacterial virulence systems are progressing from the discovery stage through the FDA approval process. Here we review novel antibodies that target specific virulence systems as well as a variety of newly discovered small molecules that block bacterial attachment, communication systems (quorum sensing) or important regulatory processes associated with virulence gene expression.Summary-The success of novel therapeutics could significantly change clinical practice. Furthermore, the complications of collateral damage due to antibiotic administration e.g. suprainfections or decreased host immunity due to loss of synergistic bacterial communities, may be minimized using therapeutics that specifically target pathogenic behavior.

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Pilicides — Small Molecules Targeting Bacterial Virulence

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 7 publications

References 1 publication

Multi-species biofilms: how to avoid unfriendly neighbors

Multi-species biofilms: how to avoid unfriendly neighbors

Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation

Novel strategies to combat bacterial virulence

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