Biology subjects

Rudramurthy, S. M.

Publications and source records attributed to Rudramurthy, S. M..

3 recordsLinked to original sources

bioRxiv2025

Antifungal susceptibility profile of clinically relevant species of the genus Sporothrix: establishment of Epidemiological Cutoff Values (ECVs) according to CLSI broth microdilution methodology

Sporotrichosis is a globally distributed subcutaneous mycosis caused mainly by Sporothrix brasiliensis, S. schenckii, and S. globosa. Cat-transmitted sporotrichosis, primarily caused by S. brasiliensis in South America and to a lesser extent by S. schenckii in Southeast Asia, is emerging as a significant public health concern, due its outbreak potential. Itraconazole is the first-choice drug for treatment of human and cats, but reduced susceptibility has been reported based on previously proposed epidemiological cut-off values (ECVs). To support resistance surveillance, we aimed to establish CLSI-endorsed ECVs for these clinically relevant Sporothrix species. A total of 3,588 minimum inhibitory concentration (MIC) values for seven antifungal agents (amphotericin B, itraconazole, posaconazole, voriconazole, isavuconazole, olorofim, and terbinafine) were obtained from 19 international laboratories. Four of seven antifungals met the CLSI M57 guidelines criteria to determine the ECV. Established ECVs for amphotericin B were found to be high with 8 {micro}g/mL for S. brasiliensis and S. globosa, and 4 {micro}g/mL for S. schenckii. Itraconazole ECVs were 4 {micro}g/mL for S. brasiliensis and S. schenckii. Posaconazole ECVs were 4 {micro}g/mL for all three species (tentative for S. globosa), while the terbinafine ECV for S. brasiliensis was 0.12 {micro}g/mL. Olorofim demonstrated good in vitro activity, particularly against S. brasiliensis. Overall, this study establishes validated ECVs for key antifungals against Sporothrix species and identifies a low prevalence of non-wild type (NWT) isolates, supporting ongoing antifungal resistance monitoring.

microbiology↗

bioRxiv2025

Long-read whole-genome sequencing offers novel insights into the biology, stress adaptation, and virulence of neurotropic dematiaceous fungi associated with primary cerebral phaeohyphomycosis

Primary cerebral phaeohyphomycosis (PCP) is a severe neurological infection caused by neurotropic dematiaceous fungi, affecting both immunocompetent and immunocompromised individuals. Understanding the virulence and adaptation mechanisms of these fungal pathogens is crucial for developing effective treatment strategies. This study employed Oxford Nanopore long-read sequencing to explore the genomes of Cladophialophora bantiana, Fonsecaea monophora, and Cladosporium cladosporioides, three key species associated with PCP. KEGG pathway analysis revealed significant enrichments in carbohydrate and amino acid metabolism, highlighting the metabolic versatility of these fungi. The analysis of transposable elements showed varying proportions of repeats, with C. bantiana exhibiting the highest repeat content. Additionally, the presence of diverse families of carbohydrate-active enzymes (CAZymes) emphasized their capacity for metabolizing complex carbohydrates. The analysis also identified enrichments in secondary metabolite (SM) biosynthetic gene clusters and stress adaptation pathways. All three species possess essential genes for thermal stress adaptation, such as HSP60 and HSF1, along with enzymes for detoxifying reactive oxygen species. The examination of pathogenicity-related genes uncovered a range of virulence factors, including lethal and hypervirulence genes, which raise critical concerns for human health. Functional annotations linked many of these genes to CAZymes, SMs, and stress response proteins. Furthermore, multiple efflux transporters and genes associated with antifungal resistance were identified, indicating potential adaptive mechanisms for drug resistance. This study not only advances our understanding of the genomic features of these fungi but also highlights their ecological and clinical significance, providing a foundation for future research into their pathogenicity and resistance mechanisms.

molecular biology↗

bioRxiv2023

Microevolution of clade II isolates of Candida auris highlights multifaceted intra-clade heterogeneity in acquiring resistance towards amphotericin B

Candida auris exhibits high-level resistance to amphotericin B (AmB). Mechanisms such as ergosterol biosynthesis malfunction, oxidative damage mismanagement, and increased drug efflux contribute to AmB resistance in C. auris. In this study, we experimentally evolved two East Asian drug-susceptible clade II isolates of C. auris (P2428 and CBS10913T) isolated from different geographical locations to develop resistance against AmB. We analysed alterations in karyotype, genome sequence, and gene expression profiles to uncover the mechanisms driving AmB resistance. The independently evolved clade II adaptors displayed up to 4-16-fold higher MIC50, as compared to the parental cells. AOX2 (alternative oxidase) and the cell wall integrity pathway have been identified as critical in the development of AmB resistance. However, we noted certain intra-clade heterogeneity in the associated mechanisms. While in P2428 adaptors (P-lines), the ergosterol and sphingolipid pathways appear to play a crucial role, this was not the case for CBS10913T adaptors (A-lines), which acquired resistance independent of lipid-associated changes. The transcriptomic, WGS, and phenotypic analyses also confirm that the evolved AmB-resistant isolates follow distinct trajectories for adaptation, Furthermore, unlike the fluconazole-resistant isolates, as reported previously, changes in ploidy do not seem to contribute to the differential mechanisms of AmB resistance. Overall, this study not only provides insights into the mechanisms and pathways involved in AmB resistance but also highlights intra-clade-heterogeneity that exists within clade II of C. auris. ImportanceCandida auris demonstrates significant resistance to amphotericin B (AmB) that stems from factors like alteration of ergosterol biosynthesis, perturbation of the oxidative damage response, etc. A comprehensive understanding of underlying mechanisms can be studied in a holistic manner by subjecting resistant as well as susceptible clinical isolates to a comparative genome-level analysis. An alternate and more dynamic approach is to expose susceptible isolates to a certain concentration of drug which is not lethal but can trigger the resistance mechanisms. In the present study, we evolved C. auris towards AmB and observed novel and differential mechanisms of resistance development, in two different isolates despite belonging to the same clade. This study provides insights into the intra-clade heterogeneous behavior of C. auris towards AmB.

microbiology↗