Abstract
In the fungal pathogen Aspergillus fumigatus, resistance to azole antifungals is often linked to mutations in CYP51A, a gene that encodes the azole antifungal drug target lanosterol 14α-demethylase. The aim of this study was to investigate whether similar changes could be associated with azole resistance in a Malaysian Fusarium solani species complex (FSSC) isolate collection. Most (11 of 15) clinical FSSC isolates were Neocosmospora keratoplastica and the majority (6 of 10) of environmental isolates were Neocosmospora suttoniana strains. All 25 FSSC isolates had high minimum inhibitory concentrations (MICs) for itraconazole and posaconazole, low MICs for amphotericin B, and various (1 to >32 mg/l) voriconazole susceptibilities. There was a tight association between a 23 bp CYP51A promoter deletion and high (>32 mg/l) voriconazole MICs; of 19 FSSC strains sequenced, nine isolates had voriconazole MICs > 32 mg/l, and they all contained the 23 bp CYP51A promoter deletion, although it was absent in the ten remaining isolates with low (≤12 mg/l) voriconazole MICs. Surprisingly, this association between voriconazole resistance and the 23 bp CYP51A promoter deletion held true across species boundaries. It was randomly distributed within and across species boundaries and both types of FSSC isolates were found among environmental and clinical isolates. Three randomly selected N. keratoplastica isolates with low (≤8 mg/l) voriconazole MICs had significantly lower (1.3–7.5 times) CYP51A mRNA expression levels than three randomly selected N. keratoplastica isolates with high (>32 mg/l) voriconazole MICs. CYP51A expression levels, however, were equally strongly induced (~6,500-fold) by voriconazole in two representative strains reaching levels, after 80 min of induction, that were comparable to those of CYP51B. Our results suggest that FSSC isolates with high voriconazole MICs have a 23 bp CYP51A promoter deletion that provides a potentially useful marker for voriconazole resistance in FSSC isolates. Early detection of possible voriconazole resistance is critical for choosing the correct treatment option for patients with invasive fusariosis.
Highlights
There is heightened concern about invasive mould infections (IMIs) as a consequence of the increasing number of immunocompromised patients (Lass-Flörl and Cuenca-Estrella, 2017; Rotjanapan et al, 2018)
Thirteen of the 25 Fusarium solani species complex (FSSC) isolates were classified as N. keratoplastica (FSSC 2), five as N. falciformis (FSSC 3+4), six as N. suttoniana (FSSC 20), and one as N. petroliphila (FSSC 1) (Table 1)
The in vitro VRC susceptibilities divided into two groups: 14 group I isolates with MICVRCs ≤ 12 mg/l and 11 group II isolates that did not respond to VRC at all (MICs > 32 mg/l; Table 2)
Summary
There is heightened concern about invasive mould infections (IMIs) as a consequence of the increasing number of immunocompromised patients (Lass-Flörl and Cuenca-Estrella, 2017; Rotjanapan et al, 2018). Fusaria are among the most frequent cause of IMIs after aspergilli (Nucci and Anaissie, 2007). The Fusarium solani species complex (FSSC) comprises more than 60 species and accounts for ∼60% of fusariosis cases worldwide (O’Donnell et al, 2010; Schroers et al, 2016). In Singapore, an outbreak of contact lens associated keratitis caused by FSSC species occurred in 2005 involving 66 patients (Jureen et al, 2008). An epidemiological study in Japan, from 1998 to 2015, found that FSSC species accounted for 72.6% of all fusariosis cases, of which 77.8% were invasive fusariosis (IF) (Muraosa et al, 2017). SandovalDenis and Crous proposed renaming species of the FSSC because they belong to the related Neocosmospora genus (Sandoval-Denis and Crous, 2018); Fusarium petroliphilium (FSSC 1 clade) was renamed N. petroliphila, F. keratoplasticum (FSSC 2 clade) was renamed N. keratoplastica, F. falciforme (FSSC 3 clade) was renamed N. falciformis, and strains of the FSSC 7, 20 and 43 clades were named N. gamsii, N. suttoniana, and N. catenate, respectively (Sandoval-Denis and Crous, 2018)
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