scholarly journals Effects of Hsp90 Inhibitor Ganetespib on Inhibition of Azole-Resistant Candida albicans

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Yuan ◽  
Jie Tu ◽  
Chunquan Sheng ◽  
Xi Chen ◽  
Na Liu
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Inhibitory Effect ◽  
Hsp90 Inhibitor ◽  
Pcr Analysis ◽  
Fungal Hypha

Candida albicans is the most common fungal pathogen. Recently, drug resistance of C. albicans is increasingly severe. Hsp90 is a promising antifungal target to overcome this problem. To evaluate the effects of Hsp90 inhibitor ganetespib on the inhibition of azole-resistant C. albicans, the microdilution checkerboard method was used to measure the in vitro synergistic efficacy of ganetespib. The XTT/menadione reduction assay, microscopic observation, and Rh6G efflux assay were established to investigate the effects of ganetespib on azole-resistant C. albicans biofilm formation, filamentation, and efflux pump. Real-time RT-PCR analysis was employed to clarify the mechanism of antagonizing drug resistance. The in vivo antifungal efficacy of ganetespib was determined by the infectious model of azole-resistant C. albicans. Ganetespib showed an excellent synergistic antifungal activity in vitro and significantly inhibited the fungal biofilm formation, whereas it had no inhibitory effect on fungal hypha formation. Expression of azole-targeting enzyme gene ERG11 and efflux pump genes CDR1, CDR2, and MDR1 was significantly down-regulated when ganetespib was used in combination with FLC. In a mouse model infected with FLC-resistant C. albicans, the combination of ganetespib and FLC effectively reversed the FLC resistance and significantly decreased the kidney fungal load of mouse.

scholarly journals Eap1p, an Adhesin That Mediates Candida albicans Biofilm Formation In Vitro and In Vivo

2007 ◽  
Vol 6 (6) ◽  
pp. 931-939 ◽  
Author(s):  
Fang Li ◽  
Michael J. Svarovsky ◽  
Amy J. Karlsson ◽  
Joel P. Wagner ◽  
Karen Marchillo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Adhesion ◽  
Biofilm Formation ◽  
Fungal Infections ◽  
Gene Dosage ◽  
Venous Catheter ◽  
Flow Chamber ◽  
Dependent Manner

ABSTRACT Candida albicans is the leading cause of systemic fungal infections in immunocompromised humans. The ability to form biofilms on surfaces in the host or on implanted medical devices enhances C. albicans virulence, leading to antimicrobial resistance and providing a reservoir for infection. Biofilm formation is a complex multicellular process consisting of cell adhesion, cell growth, morphogenic switching between yeast form and filamentous states, and quorum sensing. Here we describe the role of the C. albicans EAP1 gene, which encodes a glycosylphosphatidylinositol-anchored, glucan-cross-linked cell wall protein, in adhesion and biofilm formation in vitro and in vivo. Deleting EAP1 reduced cell adhesion to polystyrene and epithelial cells in a gene dosage-dependent manner. Furthermore, EAP1 expression was required for C. albicans biofilm formation in an in vitro parallel plate flow chamber model and in an in vivo rat central venous catheter model. EAP1 expression was upregulated in biofilm-associated cells in vitro and in vivo. Our results illustrate an association between Eap1p-mediated adhesion and biofilm formation in vitro and in vivo.

scholarly journals Antimicrobial and anti-biofilm potencies of dermcidin-derived peptide DCD-1L against Acinetobacter baumannii: an in vivo wound healing model

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Zahra Farshadzadeh ◽  
Maryam Pourhajibagher ◽  
Behrouz Taheri ◽  
Alireza Ekrami ◽  
Mohammad Hossein Modarressi ◽  
...  
Keyword(s):  
Wound Healing ◽  
Acinetobacter Baumannii ◽  
Biofilm Formation ◽  
Histopathological Examination ◽  
Inhibitory Effect ◽  
Bacterial Attachment ◽  
Burn Wound ◽  
Conventional Antibiotics

Abstract Background The global emergence of Acinetobacter baumannii resistance to most conventional antibiotics presents a major therapeutic challenge and necessitates the discovery of new antibacterial agents. The purpose of this study was to investigate in vitro and in vivo anti-biofilm potency of dermcidin-1L (DCD-1L) against extensively drug-resistant (XDR)-, pandrug-resistant (PDR)-, and ATCC19606-A. baumannii. Methods After determination of minimum inhibitory concentration (MIC) of DCD-1L, in vitro anti-adhesive and anti-biofilm activities of DCD-1L were evaluated. Cytotoxicity, hemolytic activity, and the effect of DCD-1L treatment on the expression of various biofilm-associated genes were determined. The inhibitory effect of DCD-1L on biofilm formation in the model of catheter-associated infection, as well as, histopathological examination of the burn wound sites of mice treated with DCD-1L were assessed. Results The bacterial adhesion and biofilm formation in all A. baumannii isolates were inhibited at 2 × , 4 × , and 8 × MIC of DCD-1L, while only 8 × MIC of DCD-1L was able to destroy the pre-formed biofilm in vitro. Also, reduce the expression of genes involved in biofilm formation was observed following DCD-1L treatment. DCD-1L without cytotoxic and hemolytic activities significantly reduced the biofilm formation in the model of catheter-associated infection. In vivo results showed that the count of A. baumannii in infected wounds was significantly decreased and the promotion in wound healing by the acceleration of skin re-epithelialization in mice was observed following treatment with 8 × MIC of DCD-1L. Conclusions Results of this study demonstrated that DCD-1L can inhibit bacterial attachment and biofilm formation and prevent the onset of infection. Taking these properties together, DCD-1L appears as a promising candidate for antimicrobial and anti-biofilm drug development.

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection

2021 ◽  
Author(s):  
Pingping Jia ◽  
Yi Zhang ◽  
Jian Xu ◽  
Mei Zhu ◽  
Shize Peng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterial Infection ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Dependent Manner ◽  
High Potency ◽  
Resistance Development

Abstract Background Resistance to anti-tuberculosis (TB) drug is a major issue in TB control, and demands the discovery of new drugs targeting virulence factor ESX-1. Methods We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacterium and reducing bacterial virulence. We further investigated the probability of inducing drug-resistance and the underlying mechanism using M-PFC. Results A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drug, and exhibit high potency against chronic mycobacterial infection. Conclusion Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

scholarly journals Targeting Fibronectin To Disrupt In Vivo Candida albicans Biofilms

2016 ◽  
Vol 60 (5) ◽  
pp. 3152-3155 ◽  
Author(s):  
Jeniel E. Nett ◽  
Jonathan Cabezas-Olcoz ◽  
Karen Marchillo ◽  
Deane F. Mosher ◽  
David R. Andes
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Drug Targets ◽  
Venous Catheter ◽  
Surface Adhesion ◽  
Inhibitory Protein ◽  
Content Type ◽  
Novel Target

ABSTRACTNew drug targets are of great interest for the treatment of fungal biofilms, which are routinely resistant to antifungal therapies. We theorized that the interaction ofCandida albicanswith matricellular host proteins would provide a novel target. Here, we show that an inhibitory protein (FUD) targetingCandida-fibronectin interactions disrupts biofilm formationin vitroandin vivoin a rat venous catheter model. The peptide appears to act by blocking the surface adhesion ofCandida, halting biofilm formation.

scholarly journals In Vivo Inhibitory Effect on the Biofilm Formation of Candida albicans by Liverwort Derived Riccardin D

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e35543 ◽  
Author(s):  
Yan Li ◽  
Yukui Ma ◽  
Li Zhang ◽  
Feng Guo ◽  
Lei Ren ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Inhibitory Effect

scholarly journals Oral Administration of the Broad-Spectrum Antibiofilm Compound Toremifene Inhibits Candida albicans and Staphylococcus aureus Biofilm FormationIn Vivo

2014 ◽  
Vol 58 (12) ◽  
pp. 7606-7610 ◽  
Author(s):  
Kaat De Cremer ◽  
Nicolas Delattin ◽  
Katrijn De Brucker ◽  
Annelies Peeters ◽  
Soña Kucharíková ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Broad Spectrum ◽  
Staphylococcus Epidermidis ◽  
Biofilm Formation ◽  
Candida Krusei ◽  
Content Type ◽  
And Staphylococcus Aureus

ABSTRACTWe here report on thein vitroactivity of toremifene to inhibit biofilm formation of different fungal and bacterial pathogens, includingCandida albicans,Candida glabrata,Candida dubliniensis,Candida krusei,Pseudomonas aeruginosa,Staphylococcus aureus, andStaphylococcus epidermidis. We validated thein vivoefficacy of orally administered toremifene againstC. albicans and S. aureusbiofilm formation in a rat subcutaneous catheter model. Combined, our results demonstrate the potential of toremifene as a broad-spectrum oral antibiofilm compound.

scholarly journals Inhibitory Effect of Morin Against Candida albicans Pathogenicity and Virulence Factor Production: An in vitro and in vivo Approaches

2020 ◽  
Vol 11 ◽  
Author(s):  
Gurusamy Abirami ◽  
Rajaiah Alexpandi ◽  
Ravindran Durgadevi ◽  
Arunachalam Kannappan ◽  
Arumugam Veera Ravi
Keyword(s):  
Candida Albicans ◽  
Virulence Factor ◽  
Inhibitory Effect ◽  
Factor Production ◽  
Virulence Factor Production

scholarly journals The Heat-Induced Molecular Disaggregase Hsp104 of Candida albicans Plays a Role in Biofilm Formation and Pathogenicity in a Worm Infection Model

2012 ◽  
Vol 11 (8) ◽  
pp. 1012-1020 ◽  
Author(s):  
Alessandro Fiori ◽  
Soňa Kucharíková ◽  
Gilmer Govaert ◽  
Bruno P. A. Cammue ◽  
Karin Thevissen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stress Responses ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Elevated Temperatures ◽  
Structural Defects ◽  
Infection Model ◽  
Content Type

ABSTRACT The consequences of deprivation of the molecular chaperone Hsp104 in the fungal pathogen Candida albicans were investigated. Mutants lacking HSP104 became hypersusceptible to lethally high temperatures, similarly to the corresponding mutants of Saccharomyces cerevisiae , whereas normal susceptibility was restored upon reintroduction of the gene. By use of a strain whose only copy of HSP104 is an ectopic gene under the control of a tetracycline-regulated promoter, expression of Hsp104 prior to the administration of heat shock could be demonstrated to be sufficient to confer protection from the subsequent temperature increase. This result points to a key role for Hsp104 in orchestrating the cell response to elevated temperatures. Despite their not showing evident growth or morphological defects, biofilm formation by cells lacking HSP104 proved to be defective in two established in vitro models that use polystyrene and polyurethane as the substrates. Biofilms formed by the wild-type and HSP104 -reconstituted strains showed patterns of intertwined hyphae in the extracellular matrix. In contrast, biofilm formed by the hsp104 Δ/ hsp104 Δ mutant showed structural defects and appeared patchy and loose. Decreased virulence of the hsp104 Δ/ hsp104 Δ mutant was observed in the Caenorhabditis elegans infection model, in which high in vivo temperature does not play a role. In agreement with the view that stress responses in fungal pathogens may have evolved to provide niche-specific adaptation to environmental conditions, these results provide an indication of a temperature-independent role for Hsp104 in support of Candida albicans virulence, in addition to its key role in governing thermotolerance.

scholarly journals Function of Candida albicans Adhesin Hwp1 in Biofilm Formation

2006 ◽  
Vol 5 (10) ◽  
pp. 1604-1610 ◽  
Author(s):  
Clarissa J. Nobile ◽  
Jeniel E. Nett ◽  
David R. Andes ◽  
Aaron P. Mitchell
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Biofilm Formation ◽  
Tight Binding ◽  
Surface Protein ◽  
Venous Catheter ◽  
Cell Surface Protein ◽  
Additional Support

ABSTRACT Hwp1 is a well-characterized Candida albicans cell surface protein, expressed only on hyphae, that mediates tight binding to oral epithelial cells. Prior studies indicate that HWP1 expression is dependent upon Bcr1, a key regulator of biofilm formation. Here we test the hypothesis that Hwp1 is required for biofilm formation. In an in vitro model, the hwp1/hwp1 mutant produces a thin biofilm that lacks much of the hyphal mass found in the hwp1/HWP1 reconstituted strain. In a biofilm cell retention assay, we find that the hwp1/hwp1 mutant is defective in retention of nonadherent bcr1/bcr1 mutant cells. In an in vivo rat venous catheter model, the hwp1/hwp1 mutant has a severe biofilm defect, yielding only yeast microcolonies in the catheter lumen. These properties of the hwp1/hwp1 mutant are consistent with its role as a hypha-specific adhesin and indicate that it is required for normal biofilm formation. Overexpression of HWP1 in a bcr1/bcr1 mutant background improves adherence in the in vivo catheter model. This finding provides additional support for the model that Hwp1 is critical for biofilm adhesion. Hwp1 is the first cell surface protein known to be required for C. albicans biofilm formation in vivo and is thus an excellent therapeutic target.

scholarly journals Anti-adhesive and anti-biofilm activity of NC-E08. In vitro and in vivo study using Galleria mellonella infection model

2019 ◽  
Author(s):  
Gabriela Fernanda Bombarda ◽  
Janaina de Cássia Orlandi Sardi ◽  
Pedro L. Rosalen ◽  
Josy G. Lazarini ◽  
Eder R. Paganini ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Early Childhood Caries ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Oral Diseases ◽  
Antimicrobial Drugs ◽  
Structural Analogues

Biofilms are organized microbial communities formed from an ecological succession. Biofilm formation functions as a mechanism of virulence and favors the development of diseases, including oral diseases such as dental caries and periodontal disease, in which the microorganisms Streptococcus mutans and Candida albicans are closely related. Previous studies have shown that interactions between S. mutans and C. albicans are associated with the pathogenesis of early childhood caries (ECC). Therefore, there is a great interest in finding new prototypes for antimicrobial drugs, mainly for the development of structural analogues of chalcones, which constitute one of the largest classes of natural products belonging to the flavonoid family and are considered strategic molecules for this purpose.

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