Antifungal Resistance in Cryptococcal Infections

Melhem, Marcia S. C.; Leite Júnior, Diniz Pereira; Takahashi, Juliana P. F.; Macioni, Milena Bronze; Oliveira, Lidiane de; de Araújo, Lisandra Siufi; Fava, Wellington S.; Bonfietti, Lucas X.; Paniago, Anamaria M. M.; Venturini, James; Espinel-Ingroff, Ana

doi:10.3390/pathogens13020128

Pathogens

2024

DOI: 10.3390/pathogens13020128

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Antifungal Resistance in Cryptococcal Infections

Marcia S. C. Melhem,

Diniz Pereira Leite Júnior,

Juliana P. F. Takahashi

et al.

Abstract: Antifungal therapy, especially with the azoles, could promote the incidence of less susceptible isolates of Cryptococcus neoformans and C. gattii species complexes (SC), mostly in developing countries. Given that these species affect mostly the immunocompromised host, the infections are severe and difficult to treat. This review encompasses the following topics: 1. infecting species and their virulence, 2. treatment, 3. antifungal susceptibility methods and available categorical endpoints, 4. genetic mechanism… Show more

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Cited by 3 publications

References 157 publications

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Development of ptxD /Phi as a new dominant selection system for genetic manipulation in Cryptococcus neoformans

Khongthongdam,

Phetruen,

Chanarat

2024

Microbiol Spectr

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Cryptococcus neoformans is a globally distributed pathogenic fungus posing a significant threat to immunocompromised individuals, particularly those with HIV/AIDS. Effective genetic manipulation tools are essential for understanding its biology and developing new therapies. However, current genetic tools, including the variation of versatile selectable markers, are limited. This study develops and validates the phosphite dehydrogenase gene ( ptxD )/phosphite (Phi) selection system as a non-antibiotic selectable marker for genetic manipulation in C. neoformans . A codon-optimized ptxD gene from Pseudomonas stutzeri was cloned under the TEF promoter. Using the transient CRISPR-Cas9 coupled with electroporation system, we integrated the ptxD gene into the C. neoformans genome and assessed the impact of ptxD integration on cell growth and virulence factors. The ptxD /Phi system effectively selected transformed cells on Phi-containing media. Growth assays showed that ptxD integration did not adversely affect cell growth or key virulence factors, including pleomorphism, capsule size, and melanin production. Additionally, we successfully disrupted the ADE2 gene using this system, confirming its applicability for gene deletion. Taken together, the ptxD /Phi system provides a robust and versatile tool for genetic manipulation in C. neoformans , facilitating further research into its biology and pathogenicity. IMPORTANCE Cryptococcus neoformans is a type of fungus that can cause serious illnesses in people who have weakened immune systems, like those with HIV/AIDS. To better study this fungus and find new treatments, scientists need tools to change its genes in precise ways. However, the current tools available for this are somewhat limited. This research introduces a new tool called the phosphite dehydrogenase gene/phosphite system, which does not rely on antibiotics to work. It uses a gene from a different bacterium that helps select and grow only the fungus cells that have successfully incorporated new genetic information. This is particularly useful because it does not interfere with the normal growth of the fungus or the features that make it harmful (like its ability to change shape or produce protective coatings). By making it easier and more effective to manipulate the genetics of C. neoformans , this tool opens up new possibilities for understanding how this fungus operates and for developing therapies to combat its infections. This is crucial for improving the treatment of infections in vulnerable populations.

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Development of ptxD /Phi as a new dominant selection system for genetic manipulation in Cryptococcus neoformans

Khongthongdam,

Phetruen,

Chanarat

2024

Microbiol Spectr

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Late Relapse of Previous Pulmonary Cryptococcosis With Symptoms Resembling Cerebral Infarction: A Case Report

Pinchuk,

Geginat,

Rickerts

et al. 2024

Case Reports in Infectious Diseases

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Cryptococcosis, an infection caused by Cryptococcus neoformans and Cryptococcus gattii, predominantly targets the central nervous system (CNS) in patients with AIDS but is not limited to this group. The disease can also occur in individuals with various immunosuppressive conditions, frequently involving the brain or lungs. Cryptococcal meningitis (CM) is the most common form of fungal meningoencephalitis, leading to intracerebral infections, cerebral infarction, or hydrocephalus. The clinical presentation of CM is nonspecific, and imaging features can vary significantly. This case report presents a patient with cerebral infarction, who was HIV‐negative but had been on long‐term cortisone therapy. Notably, the patient had a history of pulmonary cryptococcosis 15 years prior to cerebral involvement. When initially at our clinic, histology and culture results from brain biopsies were negative and the earlier pulmonary cryptococcosis history was unknown. Subsequently, cryptococcal antigen was detected in both serum and cerebrospinal fluid (CSF), and C. neoformans was cultivated from CSF. This case highlights the critical importance of maintaining a high index of suspicion for CM, particularly in patients with a history of previous cryptococcal infections, and it also demonstrates the possibility of false‐negative brain biopsy results due to secondary vascular events associated with CM.

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Enhancing Antifungal Drug Discovery Through Co-Culture with Antarctic Streptomyces albidoflavus Strain CBMAI 1855

Giordano,

Rodrigues,

dos Santos

et al. 2024

IJMS

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Fungal infections pose a growing public health threat, creating an urgent clinical need for new antifungals. Natural products (NPs) from organisms in extreme environments are a promising source for novel drugs. Streptomyces albidoflavus CBMAI 1855 exhibited significant potential in this regard. This study aimed to (1) assess the antifungal spectrum of the CBMAI 1855 extract against key human pathogens, (2) elicit NP production through co-cultivation with fungi, correlating the metabolites with the biosynthetic gene clusters (BGCs), and (3) perform in silico toxicity predictions of the identified compounds to analyze their suitability for drug development. The crude extract of CBMAI 1855 exhibited broad-spectrum antifungal activity. The metabolomic analysis identified antifungal NPs such as antimycin A, fungimycin, surugamides, 9-(4-aminophenyl)-3,7-dihydroxy-2,4,6-trimethyl-9-oxo-nonoic acid, and ikarugamycin, with the latter two predicted to be the most suitable for drug development. Genome mining revealed three cryptic BGCs potentially encoding novel antifungals. These BGCs warrant a detailed investigation to elucidate their metabolic products and harness their potential. CBMAI 1855 is a prolific producer of multiple antifungal agents, offering a valuable source for drug discovery. This study highlights the importance of exploring microbial interactions to uncover therapeutics against fungal infections, with a detailed exploration of cryptic BGCs offering a pathway to novel antifungal compounds.

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Antifungal Resistance in Cryptococcal Infections

Cited by 3 publications

References 157 publications

Development of ptxD /Phi as a new dominant selection system for genetic manipulation in Cryptococcus neoformans

Development of ptxD /Phi as a new dominant selection system for genetic manipulation in Cryptococcus neoformans

Late Relapse of Previous Pulmonary Cryptococcosis With Symptoms Resembling Cerebral Infarction: A Case Report

Enhancing Antifungal Drug Discovery Through Co-Culture with Antarctic Streptomyces albidoflavus Strain CBMAI 1855

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