In-vitro and in-vivo susceptibility of Aspergillus fumigatus to a novel conjugated styryl ketone

Elias Kurian Manavathu, Jonathan R. Dimmock, Sarvesh C. Vashishtha, Jessica Cutright, Pranatharthi H. Chandrasekar

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Abstract

We investigated the in-vitro and in-vivo susceptibility of Aspergillus fumigatus to the novel conjugated styryl ketone NC1175 and the results were compared with those obtained for amphotericin B and itraconazole. All 20 clinical isolates of A. fumigatus examined were susceptible to NC1175 (MIC = 5.54 ± 2.48 mg/L; range 2.92-11.68 mg/L), and the minimum lethal concentration (MLC) was only twice the MIC, suggesting that NC1175 is fungicidal. The mean MIC values of amphotericin B (1.22 ± 0.58 mg/L; range 0.5-4 mg/L) and itraconazole (0.37 ± 0.11 mg/L; range 0.125-0.5 mg/L) were approximately nine- and 22-fold, respectively, lower than that of NC1175. Both amphotericin B-resistant (n = 18) and itraconazole-resistant (n = 28) isolates of A. fumigatus were as susceptible to NC1175 as amphotericin B-, and itraconazole-susceptible isolates. Kill curve experiments revealed that NC1175 at 23.35 mg/L (approximately four times the MIC) killed ≥ 99% of conidia within 24 h of exposure to the drug. The in-vivo susceptibility of A. fumigatus to NC1175 was investigated using a murine pulmonary aspergillosis model. Treatment of infected mice with amphotericin B or NC1175 did not result in significant improvement of the mean survival (amphotericin B, 7.05 ± 0.07 days; NC1175, 6.65 ± 1.25 days) of the animals compared with that of the placebo group (7.21 ± 1.20 days). However, semiquantitative organ culture revealed that clearance of A. fumigatus occurred in 16.6%, 50% and 66.6% of the mice treated with placebo, NC1175 and amphotericin B, respectively (P value for the control and the treated groups < 0.01). These results suggest that NC1175 has in-vivo and in-vitro activity against A. fumigatus and can be used as a prototypic molecule for further development as an antifungal agent.

Original languageEnglish (US)
Pages (from-to)585-590
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume42
Issue number5
DOIs
StatePublished - Nov 1 1998

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ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Manavathu, E. K., Dimmock, J. R., Vashishtha, S. C., Cutright, J., & Chandrasekar, P. H. (1998). In-vitro and in-vivo susceptibility of Aspergillus fumigatus to a novel conjugated styryl ketone. Journal of Antimicrobial Chemotherapy, 42(5), 585-590. https://doi.org/10.1093/jac/42.5.585