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New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri.

ABSTRACT: Invasive aspergillosis (IA) is a severe condition mainly caused by Aspergillus fumigatus, although other species of the genus, such as section Nigri members, can also be involved. Voriconazole (VRC) is the recommended treatment for IA; however, the prevalence of azole-resistant Aspergillus isolates has alarmingly increased in recent years, and the underlying resistance mechanisms in non-fumigatus species remain unclear. We have determined the in vitro susceptibility of 36 strains from section Nigri to VRC, posaconazole (POS), and itraconazole (ITC), and we have explored the role of Cyp51A and Cyp51B, both targets of azoles, in azole resistance. The three drugs were highly active; POS displayed the best in vitro activity, while ITC and VRC showed MICs above the established epidemiological cutoff values in 9 and 16% of the strains, respectively. Furthermore, expression studies of cyp51A and cyp51B in control condition and after VRC exposure were performed in 14 strains with different VRC susceptibility. We found higher transcription of cyp51A, which was upregulated upon VRC exposure, but no correlation between MICs and cyp51 transcription levels was observed. In addition, cyp51A sequence analyses revealed nonsynonymous mutations present in both, wild-type and non-wild-type strains of A. niger and A. tubingensis Nevertheless, a few mutations were exclusively present in non-wild-type A. tubingensis strains. Altogether, our results suggest that azole resistance in section Nigri is not clearly explained by Cyp51A protein alteration or by cyp51 gene upregulation, which indicates that other mechanisms might be involved.

SUBMITTER: Perez-Cantero A

PROVIDER: S-EPMC6591626 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Project description:Four new species, Aspergillus eucalypticola, A. neoniger, A. fijiensis and A. indologenus are described and illustrated. Aspergillus eucalypticola was isolated from Eucalyptus leaf from Australia, and is related to A. tubingensis and A. costaricaensis, but could clearly be distinguished from them based on either ?-tubulin or calmodulin sequence data. Aspergillus eucalypticola produced pyranonigrin A, funalenone, aurasperone B and other naphtho-?-pyrones. Aspergillus neoniger is also a biseriate species isolated from desert sand in Namibia, and mangrove water in Venezuela, which produces aurasperone B and pyranonigrin A. Aspergillus fijiensis is a uniseriate species related to A. aculeatinus, and was isolated from soil in Fiji, and from Lactuca sativa in Indonesia. This species is able to grow at 37 °C, and produces asperparalines and okaramins. Aspergillus indologenus was isolated from soil, India. This species also belongs to the uniseriate group of black aspergilli, and was found to be related to, but clearly distinguishable from A. uvarum based on ?-tubulin, calmodulin and ITS sequence data. Aspergillus indologenus produced the insecticidal compounds okaramins A, B, H, and two types of indol-alkaloids which have not been structure elucidated. Two other species, A. violaceofuscus and A. acidus, are revalidated based on molecular and extrolite data. Aspergillus violaceofuscus was found to be related to A. japonicus, and produced some of the same interesting indol-alkaloids as A. indologenus, and also produced several families of partially characterised extrolites that were also found in A. heteromorphus. Aspergillus acidus (previously known as A. foetidus var. pallidus and A. foetidus var. acidus) is also a valid species, while A. foetidus is a synonym of A. niger based on molecular and physiological data. Two other species described previously, A. coreanus and A. lacticoffeatus, were found to be colour mutants of A. acidus and A. niger, respectively. Methods which could be used to distinguish the two closely related and economically important species A. niger and A. awamori are also detailed. Although these species differ in their occurrence and several physiological means (elastase activities, abilities to utilise 2-deoxy-D-glucose as sole carbon source), our data indicate that only molecular approaches including sequence analysis of calmodulin or ?-tubulin genes, AFLP analysis, UP-PCR analysis or mtDNA RFLP analysis can be used reliably to distinguish these sibling species. Aspergillus section Nigri now includes 26 taxa.

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New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri.

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