Ciclopirox olamine: an antifungal alternative against cryptococcosis

Oliveira, Paulo César de; Medeiros, Caroline Sanuzi Quirino; Macêdo, Danielle Patrícia Cerqueira; Andrade, Suanni Lemos de; Correia, M.T.A.L.; Mesquita, Suzana de Fátima Paccola; Lima-Neto, Reginaldo Gonçalves de; Neves, Rejane Pereira

doi:10.1111/j.1472-765x.2010.02914.x

Cited by 9 publications

(6 citation statements)

References 20 publications

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Section: Resultssupporting

confidence: 88%

“…15 A preclinical study examined the efficacy of CPO against 16 clinical strains of C. neoformans and measured fungicidal minimal inhibitory concentrations (MICs) between 0.5 and 4 μg/mL (2−16 μM). 16 We believe that this chemical scaffold is worth exploring for developing potentially new and more effective inhibitors of C. neoformans. We synthesized 10 HPO derivatives (Table 1) of CPO to explore the preliminary structure−activity relationships (SAR) with respect to their efficacy as an antifungal agent and toxicity in mammalian cell culture.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This corresponds to the killing of 99.9% of the cells and confirms the fungicidal property of the HPO derivatives, as well as CPO, as had been observed previously in C. neoformans and other fungi. 8,15,16 HPO Derivatives are Additive with AMB and FLC. We next asked if the HPO inhibition of C. neoformans is altered when combined with the approved antifungal drugs AMB or FLC.…”

Section: ■ Introductionmentioning

confidence: 99%

“…A preclinical study examined the efficacy of CPO against 16 clinical strains of C. neoformans and measured fungicidal minimal inhibitory concentrations (MICs) between 0.5 and 4 μg/mL (2–16 μM) . We believe that this chemical scaffold is worth exploring for developing potentially new and more effective inhibitors of C.…”

Section: Introductionmentioning

confidence: 99%

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Synthetic Derivatives of Ciclopirox are Effective Inhibitors ofCryptococcus neoformans

et al. 2021

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Opportunistic fungal infections caused by Cryptococcus neoformans are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 N-hydroxypyridone derivatives to develop an initial structure–activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight of the ten show inhibition at 1–3 μM concentration (0.17–0.42 μg per mL) in both Cryptococcus species and in C. albicans, but poor activity in the Malassezia species. In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure–activity relationship points to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.

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Section: Resultssupporting

confidence: 88%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthetic Derivatives of Ciclopirox are Effective Inhibitors ofCryptococcus neoformans

et al. 2021

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“…An example is the hydroxypyridone antimycotic, ciclopirox olamine, used for topical treatment of mucocutanous mycoses, which has been shown to exhibit strong antimicrobial properties toward C. albicans as well as Cryptococcus spp. through chelation of iron (Niewerth et al, 2003 ; Lee et al, 2005 ; Oliveira et al, 2010 ). Repurposing this drug toward drug-resistant bacterial species has also proven to be promising (Carlson-Banning et al, 2013 ).…”

Section: Role Of Iron In Treatment Of Candida Albicans mentioning

confidence: 99%

Iron at the Centre of Candida albicans Interactions

Fourie¹,

Kuloyo²,

Mochochoko³

et al. 2018

Front. Cell. Infect. Microbiol.

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Iron is an absolute requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biological systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addition, hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addition, the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.

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