Atorvastatin as a promising anticryptococcal agent

Ribeiro, Noelly de Queiroz; Costa, Marliete Carvalho; Magalhães, Thaís Furtado Ferreira; Carneiro, Hellem Cristina Silva; Oliveira, Lorena; Fontes, Alide Caroline Lima; Santos, Julliana Ribeiro Alves; Ferreira, Gabriela Freitas; Araújo, Glaucy Rodrigues de; Alves, Vinícius; Frasés, Susana; Paixão, Tatiane Alves; Stoianoff, Maria Aparecida de Resende; Santos, Danielle Anjos dos

doi:10.1016/j.ijantimicag.2017.04.005

Cited by 44 publications

(29 citation statements)

References 38 publications

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“…According to our data, pretreatment of mice with atorvastatin is accompanied by a better prognosis in severe pneumonia induced by K. pneumoniae infection. These data are consistent with the beneficial effect of therapy with statins in other models, including septic shock induced by lipopolysaccharide (LPS) challenge or bacterial or fungal infection and sepsis triggered by cecal ligation and puncture (CLP) (42)(43)(44)(45)(46)(47). In addition, clinical trials have indicated the potential of atorvastatin in therapeutic improvement of patients with pneumonia.…”

Section: Discussionsupporting

confidence: 70%

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Paula

Santos

Arifa

et al. 2018

Antimicrob Agents Chemother

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The clinical pathogen is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant , based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.

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Section: Discussionsupporting

confidence: 70%

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Paula

Santos

Arifa

et al. 2018

Antimicrob Agents Chemother

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“…The phagocytic index was determined as the number of internalized yeast cells per 100 mononuclear cells and results were expressed as a percentage. Further, bone marrow-derived macrophages (BMDM) were isolated as described previously (Ribeiro et al, 2017 ). Briefly, bone marrow cells recovered from mice femurs and tibias were counted using a hemocytometer and the concentration adjusted to 2 × 10 6 cells/mL for incubation in BMM medium (RPMI supplemented with 30% L929 growth conditioning media, 20% bovine fetal serum [Gibco], 2 mM glutamine [Sigma-Aldrich], 25 mM HEPES pH 7.2, 100 units/mL of penicillin-streptomycin [Life Technologies]).…”

Section: Methodsmentioning

confidence: 99%

“…BMDMs then were lysed with 200 μL of sterile distilled water for 30 min at 37°C, and 50 μL of this suspension were plated on SDA for CFU determination. The IPR was calculated as the quotient of the CFU/mL at 24 and 3 h post Cg inoculation (Ma et al, 2009 ; Ribeiro et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Influenza A Virus as a Predisposing Factor for Cryptococcosis

Oliveira

Costa

Magalhães

et al. 2017

Front. Cell. Infect. Microbiol.

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Influenza A virus (IAV) infects millions of people annually and predisposes to secondary bacterial infections. Inhalation of fungi within the Cryptococcus complex causes pulmonary disease with secondary meningo-encephalitis. Underlying pulmonary disease is a strong risk factor for development of C. gattii cryptococcosis though the effect of concurrent infection with IAV has not been studied. We developed an in vivo model of Influenza A H1N1 and C. gattii co-infection. Co-infection resulted in a major increase in morbidity and mortality, with severe lung damage and a high brain fungal burden when mice were infected in the acute phase of influenza multiplication. Furthermore, IAV alters the host response to C. gattii, leading to recruitment of significantly more neutrophils and macrophages into the lungs. Moreover, IAV induced the production of type 1 interferons (IFN-α4/β) and the levels of IFN-γ were significantly reduced, which can be associated with impairment of the immune response to Cryptococcus during co-infection. Phagocytosis, killing of cryptococci and production of reactive oxygen species (ROS) by IAV-infected macrophages were reduced, independent of previous IFN-γ stimulation, leading to increased proliferation of the fungus within macrophages. In conclusion, IAV infection is a predisposing factor for severe disease and adverse outcomes in mice co-infected with C. gattii.

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“…Furthermore, a variety of Candida strains that were resistant to fluconazole and nystatin were all sensitive to atorvastatin [38]. Atorvastatin combined with fluconazole improved cryptococcosis caused by Cryptococcus gattii and mice treated with atorvastatin had increased survival and better clinical outcomes; this was mediated via modifications in the capsule and cell membrane in the presence of a statin that induced cell death within phagocytes [39].…”

Section: Discussionmentioning

confidence: 99%

Exposure of Aspergillus fumigatus to Atorvastatin Leads to Altered Membrane Permeability and Induction of an Oxidative Stress Response

Ajdidi

Sheehan

Kavanagh

2020

JoF

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Aspergillus fumigatus is a serious cause of disease in immune-deficient patients and in those with pulmonary malfunction (e.g., cystic fibrosis (CF), asthma). Atorvastatin is a member of the statin drug family, which are the main therapeutic agents used to decrease high serum cholesterol levels by inhibiting (HMG-CoA) reductase enzyme. The aim of the work presented here was to analyse the antifungal activity of atorvastatin and assess its effect on the virulence of A. fumigatus. Atorvastatin demonstrated strong antifungal activity and reduced the growth and viability of A. fumigatus. Exposure of A. fumigatus to atorvastatin led to a reduction in ergosterol content and increased membrane permeability, as evidenced by the release of protein, amino acids and gliotoxin. Proteomic analysis revealed an increased abundance of proteins associated with an oxidative stress response, such as the glutathione s-transferase family protein (+8.43-fold), heat shock protein Hsp30/Hsp42 (+2.02-fold) and 5-demethoxyubiquinone hydroxylase, mitochondrial (+1.73-fold), as well as secondary metabolites such as isocyanide synthase A icsA (+8.52-fold) and non-ribosomal peptide synthetase fmpE (+3.06-fold). The results presented here indicate that atorvastatin has strong antifungal properties and may have potential application in the treatment of A. fumigatus infections alone or in combination with existing antifungal agents.

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Atorvastatin as a promising anticryptococcal agent

Cited by 44 publications

References 38 publications

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice

Influenza A Virus as a Predisposing Factor for Cryptococcosis

Exposure of Aspergillus fumigatus to Atorvastatin Leads to Altered Membrane Permeability and Induction of an Oxidative Stress Response

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