Inhibitors of bacterial virulence identified in a surrogate host model

Benghezal, Mohammed; Adam, E.; Lucas, Aurore; Burn, Christine; Orchard, Michael G.; Deuschel, Christine; Valentino, Emilio; Braillard, Stéphanie; Paccaud, Jean‐Pierre; Cosson, Pierre

doi:10.1111/j.1462-5822.2006.00877.x

Cited by 27 publications

(45 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the occurrence of microbial resistance to antimicrobial agents is shown to be a growing public health problem worldwide and the biggest obstacle to the success of a treatment, as it continues to reduce the number of drugs available in the market (Oliveira and Silva, 2008; Benghezal et al , 2007). This scenario demonstrates the need for the development of new antifungal agents as therapeutic alternatives to control fungal infections.…”

Section: Introductionmentioning

confidence: 99%

Antifungal activity of topical microemulsion containing a thiophene derivative

Guimarães¹,

Reis²,

Silva³

et al. 2014

Braz. J. Microbiol.

View full text Add to dashboard Cite

Fungal infections have become a major problem of worldwide concern. Yeasts belonging to the Candida genus and the pathogenic fungus Cryptococcus neoformans are responsible for different clinical manifestations, especially in immunocompromised patients. Antifungal therapies are currently based on a few chemotherapeutic agents that have problems related to effectiveness and resistance profiles. Microemulsions are isotropic, thermodynamically stable transparent systems of oil, water and surfactant that can improve the solubilization of lipophilic drugs. Taking into account the need for more effective and less toxic drugs along with the potential of thiophene derivatives as inhibitors of pathogenic fungi growth, this study aimed to evaluate the antifungal activity of a thiophene derivative (5CN05) embedded in a microemulsion (ME). The minimum inhibitory concentration (MIC) was determined using the microdilution method using amphotericin B as a control. The formulations tested (ME- blank and ME-5CN05) showed physico-chemical properties that would allow their use by the topical route. 5CN05 as such exhibited moderate or weak antifungal activity against Candida species (MIC = 270–540 μg.mL−1) and good activity against C. neoformans (MIC = 17 μg.mL−1). Candida species were susceptible to ME-5CN05 (70–140 μg.mL−1), but C. neoformans was much more, presenting a MIC value of 2.2 μg.mL−1. The results of this work proved promising for the pharmaceutical industry, because they suggest an alternative therapy against C. neoformans.

show abstract

Section: Introductionmentioning

confidence: 99%

Antifungal activity of topical microemulsion containing a thiophene derivative

Guimarães¹,

Reis²,

Silva³

et al. 2014

Braz. J. Microbiol.

View full text Add to dashboard Cite

show abstract

“…Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.Bacteria use virulence factors as tools to facilitate disease in plants, animals, and humans (14,26,30,34); one strategy to combat infection is to inhibit these factors by small-molecule therapy, thereby helping to neutralize the offending microbe (5,6,12,19,22). It is now generally appreciated that an antivirulence approach is a powerful alternative strategy for antibacterial treatment and vaccine development (27) and that it may require multiple tactics to resolve the current drug resistance dilemma (6,8).…”

mentioning

confidence: 99%

Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins

Turgeon

Jørgensen

Visschedyk

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The mono-ADP-ribosyltransferase toxins are bacterial virulence factors that contribute to many disease states in plants, animals, and humans. These toxins function as enzymes that target various host proteins and covalently attach an ADP-ribose moiety that alters target protein function. We tested compounds from a virtual screen of commercially available compounds combined with a directed poly(ADP-ribose) polymerase (PARP) inhibitor library and found several compounds that bind tightly and inhibit toxins from Pseudomonas aeruginosa and Vibrio cholerae. The most efficacious compounds completely protected human lung epithelial cells against the cytotoxicity of these bacterial virulence factors. Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.Bacteria use virulence factors as tools to facilitate disease in plants, animals, and humans (14,26,30,34); one strategy to combat infection is to inhibit these factors by small-molecule therapy, thereby helping to neutralize the offending microbe (5,6,12,19,22). It is now generally appreciated that an antivirulence approach is a powerful alternative strategy for antibacterial treatment and vaccine development (27) and that it may require multiple tactics to resolve the current drug resistance dilemma (6,8). Antivirulence compounds offer significant advantages over conventional antibiotics since these inhibitors are directed toward specific mechanisms (targets) in the offending pathogen that promote infection rather than against an essential metabolic factor (12). Neutralizing the cytotoxic properties of virulence factors from microorganisms without threatening their survival offers reduced selection pressure, making the induction of drug resistance mutations less likely (6). Additionally, virulence-specific therapeutics avoid the undesirable effects on the host microbiota that are associated with current antibiotics.The mono-ADP-ribosyltransferase (mART) family is a group of toxic bacterial enzymes, some of which possess a long history against human civilization. The best-characterized and wellknown members of this lethal family are cholera toxin (CT) from Vibrio cholerae, diphtheria toxin (DT) produced by Corynebacterium diphtheriae, pertussis toxin (PT) from Bordella pertussis, heat-labile enterotoxin from Escherichia coli, C3-like exoenzyme produced by Clostridium botulinum and Clostridium limosum, and exotoxin A (ExoA) from Pseudomonas aeruginosa. These enzymes act on NAD ϩ and facilitate the scission of the glycosidic bond (C-N) between nicotinamide and its conjugated ribose followed by the transfer of the ADPribose group to a nucleophilic residue on a target macromolecule (35). This family can be divided into the CT and DT groups. The CT group consists of an ExoS-like subgroup (enzymatic A domain alone or paired with ano...

show abstract

“…Ciliates and other protozoa have been considered as training grounds for intracellular bacterial pathogens [71]. Therefore, ciliates can serve as experimental surrogates for phagocytic cells of vertebrates and ciliate cultures can be used to explore the cellular basis of bacterial pathogenesis in animals [72].…”

Section: Ciliates Interacting With Fish Microbial and Viral Pathogensmentioning

confidence: 99%

Use of Cell Cultures to Study the Interactions of Ciliates with Fish

Pinheiro¹,

Bols²

2013

Springer Science Reviews

View full text Add to dashboard Cite

How the ciliates of fish can be cultured and be used to study ciliate/fish interactions are reviewed. The culturing of ciliates is currently done in basal solutions based on either freshwater, seawater, or bodily fluids of vertebrates. These are supplemented either with bacteria, fish cells, or organic matter, which can be defined or more commonly undefined, with proteose peptone being a prominent example. Among pathogenic ciliates, the most difficult to culture has been Ichthyophthirius multifiliis. To contrast, Cryptocaryon irritans caused a similar disease and has been maintained successfully in co-cultures with fish cells. Pathogenic scuticociliates and tetrahymenas are more amenable to culture, and can be grown axenically. These cultures have been used to study pathogenic mechanisms and to screen drugs for their potential chemotherapeutic value. Ciliates may act directly on fish to cause disease, but may also influence fish health indirectly through their interactions with other types of fish pathogens, for example bacteria and fungi. For example, in culture Tetrahymena spp. have been shown to phagocytose pathogenic bacteria, Yersinia ruckerii, and microsporidia, Glugea hertwigi, where ciliates are not linked to disease, very different ciliate/fish interactions are possible. For some fish larvae, free-living ciliates are a source of nutrients. Large-scale cultures of both freshwater and marine ciliates have been achieved and could be a source of feed for fish larvae in aquaculture. Finally, ciliates have the potential to feed on fish carcasses and in doing so make nutrients available to the ecosystem. In the future cell cultures should be invaluable in studying these and other possible relationships between fish and ciliates.

show abstract

Inhibitors of bacterial virulence identified in a surrogate host model

Cited by 27 publications

References 26 publications

Antifungal activity of topical microemulsion containing a thiophene derivative

Antifungal activity of topical microemulsion containing a thiophene derivative

Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins

Use of Cell Cultures to Study the Interactions of Ciliates with Fish

Contact Info

Product

Resources

About