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

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Abstract

Candida species are a leading source of healthcare infections globally. The limited number of antifungal drugs combined with the isolation of Candida species, namely C. albicans and C. auris, exhibiting resistance to current antifungals necessitates the development of new therapeutics. The present study tested 85 synthetic phenylthiazole small molecules for antifungal activity against drug-resistant C. albicans. Compound 1 emerged as the most potent molecule, inhibiting growth of C. albicans and C. auris strains at concentrations ranging from 0.25–2 µg/mL. Additionally, compound 1 inhibited growth of other clinically-relevant yeast ( Cryptococcus) and molds ( Aspergillus) at a concentration as low as 0.50 µg/mL. Compound 1 exhibited rapid fungicidal activity, reducing the burden of C. albicans and C. auris below the limit of detection within 30 minutes. Compound 1 exhibited potent antibiofilm activity, similar to amphotericin B, reducing the metabolic activity of adherent C. albicans and C. auris biofilms by more than 66% and 50%, respectively. Furthermore, compound 1 prolonged survival of Caenorhabditis elegans infected with strains of C. albicans and C. auris, relative to the untreated control. The present study highlights phenylthiazole small molecules, such as compound 1, warrant further investigation as novel antifungal agents for drug-resistant Candida infections.

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Most cited references 31

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A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing.

Grogan R. Tristan, Eilidh Mowat, Brian G Pierce … (2007)

The incidence of fungal infections has increased significantly over the past decades. Very often these infections are associated with biofilm formation on implanted biomaterials and/or host surfaces. This has important clinical implications, as fungal biofilms display properties that are dramatically different from planktonic (free-living) populations, including increased resistance to antifungal agents. Here we describe a rapid and highly reproducible 96-well microtiter-based method for the formation of fungal biofilms, which is easily adaptable for antifungal susceptibility testing. This model is based on the ability of metabolically active sessile cells to reduce a tetrazolium salt (2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide) to water-soluble orange formazan compounds, the intensity of which can then be determined using a microtiter-plate reader. The entire procedure takes approximately 2 d to complete. This technique simplifies biofilm formation and quantification, making it more reliable and comparable among different laboratories, a necessary step toward the standardization of antifungal susceptibility testing of biofilms.

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The direct cost and incidence of systemic fungal infections.

Leslie Wilson, Carolina M Reyes, Michelle Stolpman … (2015)

In this study we determined the incidence and direct inpatient and outpatient costs of systemic fungal infections (candidiasis, aspergillosis, cryptococcosis, histoplasmosis) in 1998. Using primarily the National Hospital Discharge Survey (NHDS) for incidence and the Maryland Hospital Discharge Data Set (MDHDDS) for costs, we surveyed four systemic fungal infections in patients who also had HIV/AIDS, neoplasia, transplant, and all other concomitant diagnoses. Using a case-control method, we compared the cases with controls (those without fungal infections with the same underlying comorbidity) to obtain the incremental hospitalization costs. We used the Student's t-test to determine significance of incremental hospital costs. We modeled outpatient costs on the basis of discharge status to calculate the total annual cost for systemic fungal infections in 1998. For 1998, the projected average incidence was 306 per million US population, with candidiasis accounting for 75% of cases. The estimated total direct cost was $2.6 billion and the average per-patient attributable cost was $31,200. The most commonly reported comorbid diagnoses with fungal infections (HIV/AIDS, neoplasms, transplants) accounted for only 45% of all infections. The cost burden is high for systemic fungal infections. Additional attention should be given to the 55% with fungal disease and other comorbid diagnoses.

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Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group.

Gregory Raymond, Y Aujard (2000)

To determine the site and bacterial epidemiology of nosocomial infections (NIs) in children. 6-month prospective study with periodic chart review during hospitalization using a uniform prospective questionnaire in each unit, analyzed at a coordinating center. 20 units in eight European countries: 5 pediatric intensive care units (PICUs), 7 neonatal units, 2 hematology-oncology units, 8 general pediatric units. All children hospitalized during the study period with an NI according to Centers for Disease Control and Prevention criteria. The overall incidence of NI was 2.5%, ranging from 1% in general pediatric units to 23.6% in PICUs. Bacteria were responsible for 68% (gram-negative bacilli, 37%; gram-positive cocci, 31%), Candida for 9%, and viruses for 22% of cases. The proportion of lower respiratory tract infections was 13% in general pediatric units and 53% in PICUs. Bloodstream infections were most frequent in neonatal units (71% of NIs) and were associated with a central venous catheter in 66% of cases. Coagulase-negative Staphylococcus (CNS) was the main pathogen. Eleven percent of NI were urinary tract infections. Gastrointestinal infections were most commonly viral and accounted for 76% of NIs in general pediatric units. The prevalence of antimicrobial resistance depended on the type of unit. The highest rates were observed in PICUs: 26.3% of Staphylococcus aureus and 89% of CNS were methicillin-resistant, and 37.5% of Klebsiella pneumoniae had an extended-spectrum beta-lactamase. Mortality due to NI was 10% in PICUs and 17% in neonatal units. We found large differences in NI frequency and microbial epidemiology in this European study. Viruses were the main pathogens in general pediatrics units. Catheter-related sepsis and CNS were frequent in newborns. A high frequency of multiresistant bacteria was observed in some units. Clinical monitoring of NIs and bacterial resistance profiles are required in all pediatric units.

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Author and article information

Contributors

Mohamed N. Seleem:

ORCID: http://orcid.org/0000-0003-0939-0458

mseleem@purdue.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 12 December 2019

Publication date PMC-release: 12 December 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 18941

Affiliations

[1 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Department of Comparative Pathobiology, , College of Veterinary Medicine, Purdue University, ; 625 Harrison St., West Lafayette, IN 47907 USA

[2 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Bindley Bioscience Center, , Purdue University, ; 1201 W State St., West Lafayette, IN 47907 USA

[3 ]ISNI 0000 0004 1937 2197, GRID grid.169077.e, Department of Medicinal Chemistry and Molecular Pharmacology, , College of Pharmacy, Purdue University, ; 575 Stadium Mall Dr., West Lafayette, IN 47907 USA

[4 ]ISNI 0000 0001 2155 6022, GRID grid.411303.4, Department of Pharmaceutical Organic Chemistry, , College of Pharmacy, Al-Azhar University, ; Cairo, 11884 Egypt

[5 ]ISNI 0000 0004 0576 5483, GRID grid.440881.1, University of Science and Technology, Nanoscience Program, Zewail City of Science and Technology, October Gardens, ; 6th of October, Giza, 12578 Egypt

[6 ]Purdue Institute of Inflammation, Immunology, and Infectious Disease, 610 Purdue Mall, West Lafayette, IN 47907 USA

Author information

Hassan E. Eldesouky http://orcid.org/0000-0003-4718-6087

Mohamed N. Seleem http://orcid.org/0000-0003-0939-0458

Article

Publisher ID: 55379

DOI: 10.1038/s41598-019-55379-1

PMC ID: 6908612

PubMed ID: 31831822

SO-VID: 43403318-939b-4c48-98fa-4001418576b2

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 September 2019

Date accepted : 26 November 2019

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ScienceOpen disciplines: Uncategorized

Keywords: phenotypic screening,fungal infection,biofilms,preclinical research

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ScienceOpen disciplines: Uncategorized

Keywords: phenotypic screening, fungal infection, biofilms, preclinical research

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

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Most cited references 31

A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing.

The direct cost and incidence of systemic fungal infections.

Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group.

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