Stress-driven emergence of heritable non-genetic drug resistance DOI Open Access
Jinglin Lucy Xie,

Sifei Yin,

Theodore S. Yang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

Abstract Drug resistance is the chief cause of treatment failure for therapies targeting chronic and infectious diseases. Whether emergence accelerated by environmental exposure to low levels therapeutics remains controversial. Here, we report a non-genetic mechanism stress adaptation that promotes heritable widely used antifungal drug fluconazole. In human fungal pathogen Candida albicans, transient subtherapeutic fluconazole doses induces protective response term para-resistance. Like conventional mechanisms, para-resistance heritable. However, it does not arise from genetic mutations can revert spontaneously. Systematic analyses para-resistant isolates suggest its key regulators include stress-activated MAP kinase Hog1, histone deacetylase subunit Snt1, chromatin regulator Rap1, Sko1 transcriptional factor. Notably, molecules disrupt biomolecular condensation prion propagation – crucial inheritance protein assemblies block induction para-resistance, whereas inhibiting deacetylases facilitates induction. We find common in clinical and, remarkably, passage through mammalian gut triggers acquisition, compromising fluconazole’s therapeutic efficacy. Our work defines pervasive, prion-like epigenetic highlights potential strategies mitigate rapid resistance.

Language: Английский

Mechanisms of resistance to cell wall and plasma membrane targeting antifungal drugs in candida species isolated in africa DOI
Chibuike Ibe, Akaninyene Otu, Carolina H. Pohl

et al.

Expert Review of Anti-infective Therapy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 14

Published: Jan. 4, 2025

There is a rise in the emergence of multidrug resistant fungal pathogens worldwide, including Africa.

Language: Английский

Citations

1
The role of gene copy number variation in antimicrobial resistance in human fungal pathogens DOI Creative Commons

Alan R. Jay,

David Jordan, Aleeza C. Gerstein

et al.

npj Antimicrobials and Resistance, Journal Year: 2025, Volume and Issue: 3(1)

Published: Jan. 6, 2025

Faced with the burden of increasing resistance to antifungals in many fungal pathogens and constant emergence new drug-resistant strains, it is essential assess importance various mechanisms. Fungi have relatively plastic genomes can tolerate genomic copy number variation (CNV) caused by aneuploidy gene amplification or deletion. In cases, these changes lead adaptation stressful conditions, including those antifungal drugs. Here, we specifically examine contribution CNVs resistance. We undertook a thorough literature search, collecting reports CNV, classifying examples CNV-conferred into four main find that human pathogens, there little evidence plays major role compared other types mutations. discuss why might be underestimating their approaches being used study them.

Language: Английский

Citations

1
Genome restructuring and lineage diversification of Cryptococcus neoformans during chronic infection of human hosts DOI Creative Commons
Marhiah C. Montoya,

Kayla Wilhoit,

Debra Murray

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Abstract Classified as a critical public health threat by the World Health Organization, Cryptococcus neo-formans infections with significant morbidity and mortality. Reports of cryptococcosis persistence, relapse, reinfection date back to 1950s, yet factors driving chronic remain poorly understood. A major challenge is scarcity serial patient specimens detailed medical records study simultaneous evolution pathogen host status. This provides first genomic phenotypic analysis in-host C. neoformans during lasting over year in six immunocompromised patients. We find fungal genome persistent infection characterized large-scale restructuring increasing heterogeneity. Phenotypic changes show diversification virulence traits antifungal susceptibility. Genotypically phenotypically distinct sub-lineages arise co-persist within same tissues, consistent model diversifying selection niche partitioning complex environment human hosts.

Language: Английский

Citations

0
Genomics insights of candidiasis: mechanisms of pathogenicity and drug resistance DOI Creative Commons
Xin Huang, Qin Dong, Qi Zhou

et al.

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 27, 2025

Candidiasis, a prevalent class of human infections caused by fungi belonging to the Candida genus, is garnering increasing attention due its pathogenicity and emergence drug resistance. The advancement genomics technologies has offered powerful tools for investigating pathogenic mechanisms resistance characteristics Candida. This comprehensive review provides an overview applications in candidiasis research, encompassing genome sequencing, comparative genomics, functional along with features core virulence factors Moreover, this highlights role genomic variations resistance, further elucidating evolutionary adaptive In conclusion, underscores current state research prospective avenues exploration candidiasis, providing theoretical basis clinical treatments public health strategies.

Language: Английский

Citations

0
Stress-driven emergence of heritable non-genetic drug resistance DOI Open Access
Jinglin Lucy Xie,

Sifei Yin,

Theodore S. Yang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

Abstract Drug resistance is the chief cause of treatment failure for therapies targeting chronic and infectious diseases. Whether emergence accelerated by environmental exposure to low levels therapeutics remains controversial. Here, we report a non-genetic mechanism stress adaptation that promotes heritable widely used antifungal drug fluconazole. In human fungal pathogen Candida albicans, transient subtherapeutic fluconazole doses induces protective response term para-resistance. Like conventional mechanisms, para-resistance heritable. However, it does not arise from genetic mutations can revert spontaneously. Systematic analyses para-resistant isolates suggest its key regulators include stress-activated MAP kinase Hog1, histone deacetylase subunit Snt1, chromatin regulator Rap1, Sko1 transcriptional factor. Notably, molecules disrupt biomolecular condensation prion propagation – crucial inheritance protein assemblies block induction para-resistance, whereas inhibiting deacetylases facilitates induction. We find common in clinical and, remarkably, passage through mammalian gut triggers acquisition, compromising fluconazole’s therapeutic efficacy. Our work defines pervasive, prion-like epigenetic highlights potential strategies mitigate rapid resistance.

Language: Английский

Citations

0