Antifungal Potential of Copper(II), Manganese(II) and Silver(I) 1,10-Phenanthroline Chelates Against Multidrug-Resistant Fungal Species Forming the Candida haemulonii Complex: Impact on the Planktonic and Biofilm Lifestyles

Candida haemulonii complex (C. haemulonii, C. duobushaemulonii and C. haemulonii var. vulnera) is well-known for its resistance profile to different available antifungal drugs. Although echinocandins are the most effective class of antifungal compounds against the C. haemulonii species complex, clinical isolates resistant to caspofungin, micafungin and anidulafungin have already been reported. In this work, we present a literature review regarding the effects of echinocandins on this emergent fungal complex. Published data has revealed that micafungin and anidulafungin were more effective than caspofungin against the species forming the C. haemulonii complex. Subsequently, we investigated the susceptibilities of both planktonic and biofilm forms of 12 Brazilian clinical isolates of the C. haemulonii complex towards caspofungin and micafungin (anidulafungin was unavailable). The planktonic cells of all the fungal isolates were susceptible to both of the test echinocandins. Interestingly, echinocandins caused a significant reduction in the biofilm metabolic activity (viability) of almost all fungal isolates (11/12, 91.7%). Generally, the biofilm biomasses were also affected (reduction range 20–60%) upon exposure to caspofungin and micafungin. This is the first report of the anti-biofilm action of echinocandins against the multidrug-resistant opportunistic pathogens comprising the C. haemulonii complex, and unveils the therapeutic potential of these compounds.

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Imidazolium salts with antifungal potential against multidrug-resistant dermatophytes

Journal of Applied Microbiology ◽

10.1111/jam.12862 ◽

2015 ◽

Vol 119 (2) ◽

pp. 377-388 ◽

Cited By ~ 20

Author(s):

D.F. Dalla Lana ◽

R.K. Donato ◽

C. Bündchen ◽

C.M. Guez ◽

V.Z. Bergamo ◽

...

Keyword(s):

Multidrug Resistant ◽

Imidazolium Salts ◽

Antifungal Potential

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Ultra-Morphological Changes of Trichophyton Rubrum Treated with Hydroxychavicol

IIUM Medical Journal Malaysia ◽

10.31436/imjm.v16i2.326 ◽

2020 ◽

Vol 16 (2) ◽

Author(s):

P. M. Ridzuan ◽

Nasir Mohamad ◽

Salwani Ismail ◽

Nor Iza A. Rahman ◽

Sanusi N.A ◽

...

Keyword(s):

Trichophyton Rubrum ◽

Morphological Changes ◽

Treated Group ◽

Fungal Species ◽

Skin Infections ◽

Betel Leaf ◽

Transmission Electron ◽

Antifungal Potential ◽

Resistant Strains ◽

Preliminary Study

Trichophyton rubrum is a common pathogenic fungal species that is responsible for causing infection on human skin, hair and nail. The antifungal-resistant strains complicate the treatment regime. Hydroxychavicol (HC) is one of the main compounds from Piper betel leaf that have antifungal potential and its mechanism of action has not been studied yet. The objective of this preliminary study to determine the antifungal properties of HC against T. rubrum using transmission electron microscope (TEM) on gross and ultrastructure of T. rubrum hypha. T. rubrum was treated with HC and miconazole (MI) at concentrations of 1.25, 2.5, 5 and 10 mg/mL for 1, 3, 5 and 7 days continuously. Generally, fungi structures became more severely damaged at increasing treatment duration. Microscopically, the fungi’s cell wall treated with HC showed a rough surface, shrinkage and demolition similar to the MI treated group. The fungi organelles were also demolished and disorganized. This study revealed that HC has the ability to inhibit T. rubrum growth and has potential to be an antifungal agent for skin infections.

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Identification of cell-associated and secreted serine-type peptidases in multidrug-resistant emergent pathogens belonging to the Candida haemulonii complex

Folia Microbiologica ◽

10.1007/s12223-018-0651-y ◽

2018 ◽

Vol 64 (2) ◽

pp. 245-255 ◽

Cited By ~ 3

Author(s):

Xênia M. Souto ◽

Lívia S. Ramos ◽

Marta H. Branquinha ◽

André L. S. Santos

Keyword(s):

Multidrug Resistant ◽

Candida Haemulonii

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Increasing Prevalence of Multidrug-Resistant Candida haemulonii Species Complex among All Yeast Cultures Collected by a Reference Laboratory over the Past 11 Years

Journal of Fungi ◽

10.3390/jof6030110 ◽

2020 ◽

Vol 6 (3) ◽

pp. 110 ◽

Cited By ~ 3

Author(s):

Soraia Lopes Lima ◽

Elaine Cristina Francisco ◽

João Nóbrega de Almeida Júnior ◽

Daniel Wagner de Castro Lima Santos ◽

Fabiane Carlesse ◽

...

Keyword(s):

Amphotericin B ◽

Species Complex ◽

Antifungal Susceptibility ◽

Its Region ◽

Multidrug Resistant ◽

Sensu Stricto ◽

Culture Collection ◽

Reference Laboratory ◽

Yeast Cultures ◽

Candida Haemulonii

There is worldwide concern with the increasing rates of infections due to multiresistant Candida isolates reported in tertiary medical centers. We checked for historical trends in terms of prevalence rates and antifungal susceptibility of the Candida haemulonii species complex in our yeast stock culture collected during the last 11 years. The isolates were identified by sequencing the rDNA internal transcribed spacer (ITS) region, and antifungal susceptibility tests for amphotericin B, voriconazole, fluconazole, anidulafungin, and 5-fluorocytosine were performed by the Clinical and Laboratory Standards Institute (CLSI) microbroth method. A total of 49 isolates were identified as Candida haemulonii sensu stricto (n = 21), followed by C. haemulonii var. vulnera (n = 15) and C. duobushaemulonii (n = 13), including 38 isolates cultured from patients with deep-seated Candida infections. The prevalence of the C. haemulonii species complex increased from 0.9% (18 isolates among 1931) in the first period (December 2008 to June 2013) to 1.7% (31 isolates among 1868) in the second period (July 2014 to December 2019) of analysis (p = 0.047). All isolates tested exhibited high minimum inhibition concentrations for amphotericin B and fluconazole, but they remained susceptible to 5-fluorocytosine and anidulafungin. We were able to demonstrate the increased isolation of the multiresistant Candida haemulonii species complex in our culture collection, where most isolates were cultured from patients with deep-seated infections.

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A second generation fungerp analog SCY-247, shows potent in vivo activity in a murine model of hematogenously disseminated Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01989-20 ◽

2020 ◽

pp. AAC.01989-20

Author(s):

Sherman Chu ◽

Lisa Long ◽

Thomas S McCormick ◽

Katyna Borroto-Esoda ◽

Stephen Barat ◽

...

Keyword(s):

Survival Rate ◽

Murine Model ◽

Second Generation ◽

Fungal Infections ◽

Plasma Concentrations ◽

Survival Rates ◽

Multidrug Resistant ◽

Fungal Species ◽

First Line Therapy

Echinocandins are a first-line therapy for Candida infections through their ability to inhibit the synthesis of polymer ß-(1,3)-D-glucan. However, there has been an emergence of multidrug-resistant fungal species necessitating the development of novel antifungal agents to combat invasive fungal infections. SCY-247, a second-generation glucan synthase inhibitor of the triterpenoid class (fungerps), is currently being developed as a potential therapy option. We determined the pharmacokinetics of SCY-247 following oral (gavage) administration in mice and evaluated the efficacy of SCY-247 in a murine model of hematogenously disseminated candidiasis caused by C. albicans. Plasma concentrations of SCY-247 were measurable through the last collected time point in all dose groups. Mean concentrations of SCY-247 increased with dose levels, with concentrations of SCY-247 higher after multiple doses compared to a single dose. Treatment with SCY-247 resulted in decreased fungal burden and improvement in survival rates against C. albicans disseminated infection. Treatment with 10 mg/kg SCY-247 showed a significant reduction in CFUs compared to the untreated control (3-log decrease on average) (P=0.008). Similarly, SCY-247 40 mg/kg demonstrated a statistically significant reduction in kidney CFUs compared to untreated mice (average log CFU ± SD of 2.38 ± 2.58 vs 6.26 ± 0.51; P=0.001). Mice treated with SCY-247 at 40 mg/kg exhibited a 100% survival rate at the end of the study, contrasted with 62.5% (5 of 8) survival rate in untreated mice. The results of this investigation indicate that SCY-247 is a promising novel anti-fungal agent with activity against Candida infections.

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Global Screening of Genomic and Transcriptomic Factors Associated with Phenotype Differences between Multidrug-Resistant and -Susceptible Candida haemulonii Strains

mSystems ◽

10.1128/msystems.00459-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 2

Author(s):

Hao Zhang ◽

Yifei Niu ◽

Jingwen Tan ◽

Weixia Liu ◽

Ming-an Sun ◽

...

Keyword(s):

Drug Resistance ◽

Cell Wall ◽

Multidrug Resistance ◽

Multidrug Resistant ◽

Antifungal Drugs ◽

Cell Wall Integrity ◽

Close Relative ◽

Content Type ◽

Candida Haemulonii ◽

Resistant Strains

ABSTRACT Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annotated the genomes of two reference strains from the C. haemulonii complex, compared the phenotypes, genomes, and transcriptomes of a triazole-susceptible and two triazole-resistant C. haemulonii strains, and identified triazole susceptibility, morphology, fitness, and the major genetic and gene expression differences between the strains. A multidrug efflux gene, CDR1, was recurrently found to be upregulated for expression in triazole-resistant strains. Blocking the activity of Cdr1 increased the susceptibility to triazoles strikingly. Comparative transcriptome analysis also demonstrated impaired cell wall integrity, filamentous growth, and iron homeostasis in triazole-resistant strains. Finally, we also identified a zinc-binding MHR family transcription regulator gene that mutated in triazole-resistant strains spontaneously, contributing to the changes of morphology and, possibly, cell wall integrity between the strains. The study provided important clues for future studies exploring the mechanisms of multidrug resistance and related phenotypic differences of C. haemulonii strains. IMPORTANCE A comprehensive, multi-omic survey was performed to disclose the genetic backgrounds and differences between multidrug-resistant and -susceptible C. haemulonii strains. Genes were identified with mutations or significant expression differences in multidrug-resistant compared to multidrug-susceptible strains, which were mainly involved in multidrug resistance, stress fitness, and morphology. The Cdr1-encoding gene, C. haemulonii 2486 (CH_2486), was expressed at a significantly increased level in multidrug-resistant strains. Functional inhibition experiments further implicated potential roles of CH_2486 in drug resistance. A gene spontaneously mutated in resistant strains, CH_4347, was experimentally validated to influence the morphology of spores, possibly by controlling cell wall integrity.

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Biocidal Resistance in Clinically Relevant Microbial Species: A Major Public Health Risk

Pathogens ◽

10.3390/pathogens10050598 ◽

2021 ◽

Vol 10 (5) ◽

pp. 598

Author(s):

Elaine Meade ◽

Mark Anthony Slattery ◽

Mary Garvey

Keyword(s):

Public Health ◽

Antimicrobial Resistance ◽

Infectious Diseases ◽

Disease Transmission ◽

Action Plan ◽

Multidrug Resistant ◽

Fungal Species ◽

Control Measures ◽

Microbial Species ◽

The Impact

Antimicrobial resistance is one of the greatest dangers to public health of the 21st century, threatening the treatment and prevention of infectious diseases globally. Disinfection, the elimination of microbial species via the application of biocidal chemicals, is essential to control infectious diseases and safeguard animal and human health. In an era of antimicrobial resistance and emerging disease, the effective application of biocidal control measures is vital to protect public health. The COVID-19 pandemic is an example of the increasing demand for effective biocidal solutions to reduce and eliminate disease transmission. However, there is increasing recognition into the relationship between biocide use and the proliferation of Antimicrobial Resistance species, particularly multidrug-resistant pathogens. The One Health approach and WHO action plan to combat AMR require active surveillance and monitoring of AMR species; however, biocidal resistance is often overlooked. ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens and numerous fungal species have demonstrated drug and biocidal resistance where increased patient mortality is a risk. Currently, there is a lack of information on the impact of biocide application on environmental habitats and ecosystems. Undoubtedly, the excessive application of disinfectants and AMR will merge to result in secondary disasters relating to soil infertility, loss of biodiversity and destruction of ecosystems.

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