Anti-virulence Strategies to Target Bacterial Infections

Mühlen, Sabrina; Dersch, Petra

doi:10.1007/82_2015_490

Cited by 142 publications

(153 citation statements)

References 247 publications

(60 reference statements)

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“…Mannosides are being rationally optimized to exhibit more drug-like pharmacokinetic properties, such as improved metabolic stability and bioavailability [74, 78]. Agents such as the so-called “anti-virulence” compounds that block specific molecular steps in pathogenesis, apply much less selective pressure on pathogenic bacteria, thereby reducing the rapidity of resistance development [79]. Further, due to their known mechanism of action, such agents can be used as tools to further probe the biology of host-pathogen interactions [80].…”

Section: Next-generation Therapeuticsmentioning

confidence: 99%

Urinary Tract Infection: Pathogenesis and Outlook

McLellan

Hunstad

2016

Trends in Molecular Medicine

266

206

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The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further complicates therapeutic decisions, necessitating new approaches based on fundamental biological investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis and how these might inform both our clinical perspective and future scientific priorities.

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Section: Next-generation Therapeuticsmentioning

confidence: 99%

Urinary Tract Infection: Pathogenesis and Outlook

McLellan

Hunstad

2016

Trends in Molecular Medicine

266

206

View full text Add to dashboard Cite

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“…[121,184,[187][188][189][190] Al arge number of small molecules have been investigated for their modulation of regulatory pathways and secretion systems.I na ddition, antibodies were specifically raised against toxins to eliminate their devastating function to host cells.A sac onsequence of their sheer number,w es olely discuss selected examples of small-molecule approaches with afocus on the past five years.…”

Section: Antivirulencementioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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“…However, despite the great efforts in developing anti-virulence compounds or in applying available PARP inhibitors for targeting ART activities involved in infectious diseases, the use of blocking antibodies still represents the gold standard treatment for neutralising bacterial toxins [63,64,[298][299][300].…”

Section: Conclusion: Targeting Toxin Adp-ribosyl Transferase Activitymentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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Anti-virulence Strategies to Target Bacterial Infections

Cited by 142 publications

References 247 publications

Urinary Tract Infection: Pathogenesis and Outlook

Urinary Tract Infection: Pathogenesis and Outlook

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Targeting ADP-ribosylation as an antimicrobial strategy

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