In vitro activity of the anthelmintic drug niclosamide against Sporothrix spp. strains with distinct genetic and antifungal susceptibility backgrounds

Ramos, Mariana Lucy Mesquita; Almeida-Silva, Fernando; de Souza Rabello, Vanessa Brito; Nahal, Juliana; Figueiredo-Carvalho, Maria Helena Galdino; Bernardes-Engemann, Andrea Reis; Poester, Vanice Rodrigues; Xavier, Melissa Orzechowski; Meyer, Wieland; Zancopé-Oliveira, Rosely Maria; Frases, Susana; Almeida-Paes, Rodrigo

doi:10.1007/s42770-024-01301-5

Cited by 2 publications

(3 citation statements)

References 68 publications

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“…Drugs tackling these factors can be suitable combination partners for salicylanilides. In addition, the high genetic variability of niclosamide-resistant S. schenckii was suggested as a possible resistance factor, in contrast to S. brasiliensis strains that are highly sensitive to niclosamide treatment [ 61 ]. In leukemia cells, a CRISPR/Cas9 library screen in the presence or absence of niclosamide identified DHODH and the heat-shock protein HspA9 (also known as mitochondrial Hsp70 and mortalin) to be overexpressed in surviving cells, and inhibitors of these targets are expected to generate synergy effects with niclosamide [ 119 ].…”

Section: Discussion Of Current Challenges and Opportunitiesmentioning

confidence: 99%

“…Blocking of biofilm formation via NDU1 inhibition, increased ROS formation, suppressed mitochondrial oxygen consumption, and protection of mice from infection [52] Trichophyton tonsurans Strong growth inhibition (MIC < 1 µM) [57] Sporothrix brasiliensis Broad-spectrum growth inhibition (MIC = 0.625-2.5 µM, wildtype and non-wildtype strains); fungicidal [60,61] Paracoccidioides brasiliensis Fungicidal (1 µM) [60] Histoplasma capsulatum Fungicidal (1 µM) [60] Madurella mycetomatis Growth inhibition of SO1 and CBS131320 isolates (MIC = 0.79-1.6 µg/mL) [66] Basidiomycetes…”

Section: Candida Aurismentioning

confidence: 99%

“…In addition, fungicidal activity was observed in 89% of the tested Sporothrix strains. The broad-spectrum activity of niclosamide against S. brasiliensis strains endemic in Brazil and to non-wildtype strains is promising, while the resistance of most S. schenckii strains to niclosamide warrants more studies on the possible resistance mechanisms of this fungus [ 61 ].…”

Section: Niclosamide: Chemistry Pharmacology and Antifungal Activitymentioning

confidence: 99%

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The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

Biersack

2024

IJMS

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Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development of new efficient drugs, and the emergence of resistant fungal strains. Niclosamide is currently applied for the treatment of worm infections. Its mechanisms of action, which include the suppression of mitochondrial oxidative phosphorylation (also known as mitochondrial uncoupling), among others, has led to a repurposing of this promising anthelmintic drug for the therapy of further human diseases such as cancer, diabetes, and microbial infections. Given the urgent need to develop new drugs against fungal infections, the considerable antifungal properties of niclosamide are highlighted in this review. Its chemical and pharmacological properties relevant for drug development are also briefly mentioned, and the described mitochondria-targeting mechanisms of action add to the current arsenal of approved antifungal drugs. In addition, the activities of further salicylanilide-based niclosamide analogs against fungal pathogens, including agents applied in veterinary medicine for many years, are described and discussed for their feasibility as new antifungals for humans. Preliminary structure–activity relationships are determined and discussed. Various salicylanilide derivatives with antifungal activities showed increased oral bioavailabilities when compared with niclosamide. The simple synthesis of salicylanilide-based drugs also vouchsafes a broad and cost-effective availability for poorer patient groups. Pertinent literature is covered until 2024.

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Section: Discussion Of Current Challenges and Opportunitiesmentioning

confidence: 99%

Section: Candida Aurismentioning

confidence: 99%

Section: Niclosamide: Chemistry Pharmacology and Antifungal Activitymentioning

confidence: 99%

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The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

Biersack

2024

IJMS

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Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives

Ma,

Veeragoni,

Ghosh

et al. 2024

Biomedicines

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The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8–1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2–0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs.

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In vitro activity of the anthelmintic drug niclosamide against Sporothrix spp. strains with distinct genetic and antifungal susceptibility backgrounds

Cited by 2 publications

References 68 publications

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives

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