Identification of a Phenylthiazole Small Molecule with Dual Antifungal and Antibiofilm Activity Against Candida albicans and Candida auris

Mohammad, Haroon; Eldesouky, Hassan E.; Hazbun, Tony R.; Mayhoub, Abdelrahman S.; Seleem, Mohamed N.

doi:10.1038/s41598-019-55379-1

Cited by 38 publications

(28 citation statements)

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“…Therefore, several agents with or without intrinsic antifungal activity were examined to determine whether they are capable of blocking biofilm production. Synthetic phenylthiazole compounds were demonstrated to possess potent antibiofilm activity against C. albicans and Candida auris [37].…”

Section: Discussionmentioning

confidence: 99%

Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production

Chen

Lee

2021

Journal of Medical Microbiology

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Introduction. Candida species can form biofilms on tissues and medical devices, making them less susceptible to antifungal agents. Hypothesis/Gap Statement. Antifungal combination may be an effective strategy to fight against Candida biofilm. Aim. In this study, we investigated the in vitro activity of fluconazole, caspofungin and amphotericin B, alone and in combination, against 17 clinical Candida tropicalis and 6 Candida parapsilosis isolates with high biofilm formation. We also tested LL-37 and lysozyme for anti-biofilm activity against a selected C. tropicalis isolate. Methodology. Candida biofilms were prepared using the 96-well plate-based method. The minimum biofilm eradication concentrations were determined for single and combined antifungal drugs. The activity of LL-37 and lysozyme was determined by visual reading for planktonic cells and using the XTT assay for biofilms. Results. Under biofilm conditions, fluconazole plus caspofungin showed synergistic effects against 60.9% (14 of 23) of the tested isolates, including 70.6% of C. tropicalis [fractional inhibitory concentration index (FICI), 0.26–1.03] and 33.3% of C. parapsilosis (FICI, 0.04–2.03) isolates. Using this combination, no antagonism was observed. Amphotericin B plus caspofungin showed no effects against 78.3% (18 of 23) of the tested isolates. Amphotericin B plus fluconazole showed no effects against 65.2% (15 of 23) of the tested isolates and may have led to antagonism against 2 C. tropicalis and 2 C. parapsilosis isolates. LL-37 and lysozyme had no effect on biofilms of the selected C. tropicalis isolate. Conclusions. We found that fluconazole plus caspofungin led to a synergistic effect against C. tropicalis and C. parapsilosis biofilms. The efficacy of the antifungal combination therapies of the proposed schemes against biofilm-associated Candida infections requires careful and constant evaluation.

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Section: Discussionmentioning

confidence: 99%

Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production

Chen

Lee

2021

Journal of Medical Microbiology

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“…To study the effect of aprepitant/itraconazole on the growth kinetics of C. auris , a time-kill assay was conducted, as previously described [ 26–29 ]. Briefly, exponential-phase C. auris AR0390 cells were diluted with RPMI 1640 medium to ~1 × 10 5 CFU/ml.…”

Section: Methodsmentioning

confidence: 99%

“…Cells treated with DMSO (1%), the drugs’ solvent, served as a negative control. Following incubation, RPMI 1640 medium was discarded and the formed biofilms were carefully washed twice with PBS before being quantified, using the XTT reduction assay [ 26 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…To assess the in vivo efficacy of the aprepitant/itraconazole combination, a C. elegans infection model was utilized as previously discribed [ 9 , 11 , 26 ]. Briefly, synchronized worms [strain AU37 genotype glp-4(bn2) I; sek-1(km4) X] at L4 phase were incubated in 5 ml of YPD broth containing C. auris AR0390 (adjusted at ~1 × 10 6 CFU/ml) for 3 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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Aprepitant, an antiemetic agent, interferes with metal ion homeostasis ofCandida aurisand displays potent synergistic interactions with azole drugs

et al. 2020

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With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris . Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro , by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis , and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris . This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.

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“…As such, these strains were used to study the antibiofilm activity of the pitavastatin-fluconazole combination. The microtiter biofilm formation assay using crystal violet was used, as previously described 4,21 . Briefly, overnight cultures of the tested Candida strains, grown in YPD broth, were diluted in RPMI 1640 medium to approximately 1 × 10 5 CFU/ml.…”

Section: Biofilm Inhibition Assaymentioning

confidence: 99%

Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species

Eldesouky

Salama

et al. 2020

Sci Rep

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the limited number of antifungals and the rising frequency of azole-resistant Candida species are growing challenges to human medicine. Drug repurposing signifies an appealing approach to enhance the activity of current antifungal drugs. Here, we evaluated the ability of Pharmakon 1600 drug library to sensitize an azole-resistant Candida albicans to the effect of fluconazole. The primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole against the test strain. Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as "repositionable hits". A follow-up analysis revealed pitavastatin displaying the most potent fluconazole chemosensitizing activity against the test strain (ΣFICI 0.05) and thus was further evaluated against 18 isolates of C. albicans (n = 9), C. glabrata (n = 4), and C. auris (n = 5). Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05-0.5). Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%. This study presents pitavastatin as a potent azole chemosensitizing agent that warrant further investigation. Candida species are the most common nosocomial fungal pathogens and are a major cause of healthcare-associated bloodstream infections 1-3. In the USA, Candida species are the fourth-leading cause of bloodstream infections 4,5. Diseases caused by Candida species can range from self-limited uncomplicated superficial lesions to a deadly form of disseminated invasive infection that is often associated with a high mortality rate (42-65%) 6. Available epidemiological data derived from several independent surveillance studies portray C. albicans and C. glabrata as the two major causes of Candida-related infections in North America and Europe 7-9. However, the recent emergence of C. auris has become a global health concern, considering its unique multidrug resistance nature, the efficient ability to colonize human tissues and to provoke several global outbreaks 10,11. Thus, C. auris was recently categorized by the US Centers for Disease Control and Prevention (CDC) as an urgent health threat 12. Treatment of systemic Candida infections is currently limited to only three major drug classes; azoles, polyenes, and echinocandins 13,14. The limited toxicity, oral bioavailability, and broad-spectrum of antifungal activities made azoles the most commonly prescribed drugs for treating and controlling Candida infections 14,15. Azoles

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Identification of a Phenylthiazole Small Molecule with Dual Antifungal and Antibiofilm Activity Against Candida albicans and Candida auris

Cited by 38 publications

References 50 publications

Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production

Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production

Aprepitant, an antiemetic agent, interferes with metal ion homeostasis ofCandida aurisand displays potent synergistic interactions with azole drugs

Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species

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