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Activities of sordarins in murine histoplasmosis
J R Graybill1, L Najvar, A Fothergill
1University of Texas Health Science Center, San Antonio, Texas. graybill@uthSCSA.edu
Abstract:
Sordarins are new antifungals which inhibit fungal protein synthesis by blocking elongation factor 2. Three compounds were evaluated in a murine model of histoplasmosis. Immune-competent mice were infected intravenously with 10(6) to 10(8) CFU of Histoplasma capsulatum yeast cells. Mice were treated either orally with sordarins or fluconazole from day 2 through 8 after infection or intraperitoneally with amphotericin B during the same period. Protection was measured by increased rates of survival for 30 days after infection or reduction of lung or kidney tissue counts 9 days after infection. All three of the antifungal drugs tested were protective compared with controls. Sordarins were effective at doses as low as 2 mg/kg of body weight/day. This novel class of drugs compared favorably with amphotericin B and fluconazole for the treatment of histoplasmosis.
Insights
New sordarin antifungals show promise for treating histoplasmosis by inhibiting fungal protein synthesis. These compounds effectively protected mice against Histoplasma capsulatum infection, comparing favorably to existing treatments.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum.
- Current treatments like amphotericin B and fluconazole have limitations.
- Novel antifungal agents are needed to combat resistant fungal infections.
Purpose of the Study:
- To evaluate the efficacy of sordarins, a new class of antifungals, in a murine model of histoplasmosis.
- To compare the effectiveness of sordarins against established antifungal drugs.
Main Methods:
- A murine model of histoplasmosis was established using intravenous infection with Histoplasma capsulatum.
- Mice were treated with oral sordarins, oral fluconazole, or intraperitoneal amphotericin B.
- Efficacy was assessed by survival rates and reduction of fungal burden in lung and kidney tissues.
Main Results:
- All tested antifungal drugs, including sordarins, demonstrated protective effects compared to controls.
- Sordarins were effective at low doses (2 mg/kg/day).
- Sordarins showed comparable efficacy to amphotericin B and fluconazole in this model.
Conclusions:
- Sordarins represent a promising new class of antifungal agents for histoplasmosis treatment.
- Their mechanism of action, inhibiting fungal protein synthesis via elongation factor 2, is effective.
- Further investigation into sordarins is warranted for clinical application against Histoplasma infections.