Lack of association between fluconazole susceptibility and ERG11 nucleotide polymorphisms in cryptococcus neoformans clinical isolates from Uganda

Abstract

Over 50% of Ugandan HIV-infected patients die due to cryptococcal meningitis [CM]-related complications. Fluconazole is the drug of choice for CM monoprophylaxis in resource-limited settings such as Uganda. Emerging fluconazole resistance linked to mutations in the Cryptococcus neoformans spp. ERG11 gene (CYP51) has been observed in Ugandan clinical isolates. Currently, the single nucleotide polymorphisms [SNPs] in Cryptococcus spp. ERG11 gene that could be responsible for fluconazole resistance are poorly characterized within the Ugandan C. neoformans spp. clinical isolates . If available, this information would be useful in management of cryptococcosis among HIV patients. This study was undertaken to profile the SNPs present in the coding region of the Cryptococcus neoformans spp and determine how such a profile relates to the fluconazole susceptibility pattern of these Cryptococcus neoformans spp ERG11 gene clinical isolates. Novel synonymous SNPs in the Cryptococcus neoformans spp. clinical isolates and two mutations: S460T and A457V were identified in the ERG11 gene. The S460T mutation is a missense mutation. 67.4% of the isolates had low IC50 values [<8μg/ml ] while 32.6%, had high IC50 value [≥ 8μg/ml] . The SNPs identified did not directly affect fluconazole resistance in vitro. The identified SNPs were not associated with differences in fluconazole IC50 values in vitro (p = 0.179)