A phenylthiazole derivative demonstrates efficacy on treatment of the cryptococcosis & candidiasis in animal models

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Abstract

Aim: In this work we test 2-(2-(cyclohexylmethylene)hydrazinyl)-4-phenylthiazole (CHT) against Cryptococcus spp. and Candida albicans . Methods: The ability of CHT to act in biofilm and also to interfere with C. albicans adhesion was evaluated, as well as the efficiency of the CHT in cryptococcosis and candidiasis invertebrate and murine models. Results & conclusion: In the present work we verified that CHT is found to inhibit Cryptococcus and C. albicans affecting biofilm in both and inhibited adhesion of Candida to human buccal cells. When we evaluated in vivo , CHT prolonged survival of Galleria mellonella after infections with Cryptococcusgattii , Cryptococcusneoformans or C. albicans and promoted a reduction in the fungal burden to the organs in the murine models. These results demonstrate CHT therapeutic potential. Lay abstract Candida spp. and Cryptococcus spp. cause thousands of deaths each year. In general, antifungal drugs have several limitations to their use, and there are a limited number of these drugs available to be used in the treatments of fungal diseases. This work contributes to the search for new antifungal drugs for the treatment of candidiasis and cryptococcosis, aiming in the future, after all necessary tests, to serve as a basis for the production of drugs that could be used in the treatment of patients with these fungal diseases. Graphical abstract

Most cited references 34

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Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.

John R. Perfect, William E. Dismukes, Francoise Dromer … (2010)

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

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Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance.

J. Chandra, D Kuhn, P. Mukherjee … (2001)

Biofilms are a protected niche for microorganisms, where they are safe from antibiotic treatment and can create a source of persistent infection. Using two clinically relevant Candida albicans biofilm models formed on bioprosthetic materials, we demonstrated that biofilm formation proceeds through three distinct developmental phases. These growth phases transform adherent blastospores to well-defined cellular communities encased in a polysaccharide matrix. Fluorescence and confocal scanning laser microscopy revealed that C. albicans biofilms have a highly heterogeneous architecture composed of cellular and noncellular elements. In both models, antifungal resistance of biofilm-grown cells increased in conjunction with biofilm formation. The expression of agglutinin-like (ALS) genes, which encode a family of proteins implicated in adhesion to host surfaces, was differentially regulated between planktonic and biofilm-grown cells. The ability of C. albicans to form biofilms contrasts sharply with that of Saccharomyces cerevisiae, which adhered to bioprosthetic surfaces but failed to form a mature biofilm. The studies described here form the basis for investigations into the molecular mechanisms of Candida biofilm biology and antifungal resistance and provide the means to design novel therapies for biofilm-based infections.

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Galleria mellonella as a model system to study Cryptococcus neoformans pathogenesis.

Eleftherios Mylonakis, Roberto Moreno, Joseph El Khoury … (2005)

Evaluation of Cryptococcus neoformans virulence in a number of nonmammalian hosts suggests that C. neoformans is a nonspecific pathogen. We used the killing of Galleria mellonella (the greater wax moth) caterpillar by C. neoformans to develop an invertebrate host model system that can be used to study cryptococcal virulence, host immune responses to infection, and the effects of antifungal compounds. All varieties of C. neoformans killed G. mellonella. After injection into the insect hemocoel, C. neoformans proliferated and, despite successful phagocytosis by host hemocytes, killed caterpillars both at 37 degrees C and 30 degrees C. The rate and extent of killing depended on the cryptococcal strain and the number of fungal cells injected. The sequenced C. neoformans clinical strain H99 was the most virulent of the strains tested and killed caterpillars with inocula as low as 20 CFU/caterpillar. Several C. neoformans genes previously shown to be involved in mammalian virulence (CAP59, GPA1, RAS1, and PKA1) also played a role in G. mellonella killing. Combination antifungal therapy (amphotericin B plus flucytosine) administered before or after inoculation was more effective than monotherapy in prolonging survival and in decreasing the tissue burden of cryptococci in the hemocoel. The G. mellonella-C. neoformans pathogenicity model may be a substitute for mammalian models of infection with C. neoformans and may facilitate the in vivo study of fungal virulence and efficacy of antifungal therapies.