Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors.
Antimicrob Agents Chemother. 2014 Mar 10;
Authors: Fernandes C, Anjos J, Walker LA, Silva BM, Cortes L, Mota M, Munro CA, Gow NA, Gonçalves T
The present work reports the effect of caspofungin, a β-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and, in response to caspofungin, its chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment the FKS1 gene was upregulated in IMF006 and down-regulated in IMF001. In addition, the resting β-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied the relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and to nikkomycin Z led to modulation of the expression of class V and class VII chitin synthase genes suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores were not affected by caspofungin. Mono-therapy with nikkomycin Z and caspofungin only provided a fungistatic inhibition, whilst the combination of both led to fungal cell lysis, revealing a strong synergistic action between chitin synthase inhibitors and β-glucan synthase inhibitors against this fungus.
PMID: 24614372 [PubMed - as supplied by publisher]