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. 2020 Jul 20;10(1):11976.
doi: 10.1038/s41598-020-68706-8.

FKS1 mutation associated with decreased echinocandin susceptibility of Aspergillus fumigatus following anidulafungin exposure

Ana Pinto E Silva  1   2 , Isabel Marcos Miranda  3 , Joana Branco  4 , Patricia Oliveira  4 , Isabel Faria-Ramos  4 , Raquel M Silva  5 , Acácio Gonçalves Rodrigues  4   6   7 , Sofia Costa-de-Oliveira  4   6
Affiliations

FKS1 mutation associated with decreased echinocandin susceptibility of Aspergillus fumigatus following anidulafungin exposure

Ana Pinto E Silva et al. Sci Rep. .

Abstract

Invasive aspergillosis (IA) is a potentially lethal infection that affects mostly immunocompromised patients caused by Aspergillus fumigatus. Echinocandins are a second-line therapy against IA, used as a salvage therapy as well as for empirical or prophylactic therapy. Although they cause lysis of growing hyphal tips, they are considered fungistatic against molds. In vivo echinocandins resistance is uncommon; however, its wide clinical use could shortly lead to the emergence of A. fumigatus resistance. The aims of the present work was to assess the development of reduced echinocandins susceptibility phenotype by a A. fumigatus strain and to unveil the molecular mechanism underlying such phenotype. We induced in vitro cross-resistance to echinocandins following exposure of A. fumigatus to anidulafungin. Stability of the resistant phenotype was confirmed after removal of anidulafungin pressure. The FKS1 gene was partially sequenced and a E671Q mutation was found. A computational approach suggests that it can play an important role in echinocandin resistance. Given the emerging importance of this mechanism for clinical resistance in pathogenic fungi, it would be prudent to be alert to the potential evolution of this resistant mechanism in Aspergillus spp infecting patients under echinocandins therapeutics.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Photographs of YEPD agar plates showing A. fumigatus colony morphology following exposure to anidulafungin. AFS, initial susceptible strain. AFR0, resistant induced strain.
Figure 2
Figure 2
Random amplification of polymorphic DNA patterns, using primers (a) OPAX and (b) R108, (c) Primer 2 and (d) OPQ6, of Aspergillus fumigatus strains (AFS, initial susceptible strain, AFR0, resistant induced strain, and AFR1, resistant strain after 30 days without antifungal) obtained during in vitro induction assay. AFC represents a distinct A. fumigatus clinical strain, with a different pattern. 100 bp DNA ladder.
Figure 3
Figure 3
Sequence and structure analysis of the E671Q substitution in Fks1p. (a) Multiple protein sequence alignment of fungal Fks1 orthologues. A potential structural and/or functional role is suggested by the conservation of E671 even in distantly related species. (b) In the predicted structural model for this domain of the Fks1 protein (amino acids 400–900), the E671Q substitution would result in the loss of polar contacts with T677, disrupting the contacts between α-helices. AFS, the initial susceptible strain is shown in green, and AFR0, the resistant induced strain is shown in blue.
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