Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment DOI

Rohith Raali,

Narsu Sivakumar,

Harsh Vardhan J.

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 14

Published: Nov. 12, 2024

Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on mucosal epithelium, most common oral malignancy. About 10% of patients within Indian subcontinent suffer from OSCC, primarily due chewing betel plant derivatives. Concomitant administration chemotherapeutic agent (Cisplatin/Paclitaxel) choice. Analysis mycobiome OSCC has projected role Candida albicans in potentiating OSCC. Hence, antifungal emerges as promising approach, these target both cells and infection. Cancer often have heightened energy requirements, targeting mitochondrial proteins disrupt division induce dysfunction contributing death, offers method treating We identified 18 targets playing crucial maintenance homeostasis. They were docked against 125 ligand molecules sourced PUBCHEM. Ligand profiling was performed using Lipinski's rule 5, SwissADME ProTox. Also, molecular dynamics MM-PBSA validate our results. Among all protein interactions, we observed DRP1 itraconazole yielded superior binding stability. Overall, lower toxicity thumping ADME properties solidified choice ligand. hope this experimental approach will enable us provide basis selecting lead molecule possible novel nano-formulation finding through in-vitro line-based testing.

Language: Английский

Metabolic regulation of the host–fungus interaction: from biological principles to therapeutic opportunities DOI Creative Commons
Rita Silva-Gomes, Inês Caldeira, Raquel Fernandes

et al.

Journal of Leukocyte Biology, Journal Year: 2024, Volume and Issue: 116(3), P. 469 - 486

Published: March 18, 2024

Abstract Fungal infections present a significant global public health concern, impacting over 1 billion individuals worldwide and resulting in more than 3 million deaths annually. Despite considerable progress recent years, the management of fungal remains challenging. The limited development novel diagnostic therapeutic approaches is largely attributed to our incomplete understanding pathogenetic mechanisms involved these diseases. Recent research has highlighted pivotal role cellular metabolism regulating interaction between fungi their hosts. In response infection, immune cells undergo complex metabolic adjustments meet energy demands necessary for an effective response. A comprehensive circuits governing antifungal immunity, combined with integration individual host traits, holds potential inform medical interventions infections. This review explores insights into immunometabolic regulation host–fungal interactions infection outcome discusses how repurposing cell function could be exploited innovative personalized approaches.

Language: Английский

Citations

5
New Polyene Macrolide Compounds from Mangrove-Derived Strain Streptomyces hiroshimensis GXIMD 06359: Isolation, Antifungal Activity, and Mechanism against Talaromyces marneffei DOI Creative Commons

Zhou Wang,

Jianglin Yin,

Meng Bai

et al.

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(1), P. 38 - 38

Published: Jan. 8, 2024

Mangrove-derived actinomycetes represent a rich source of novel bioactive natural products in drug discovery. In this study, four new polyene macrolide antibiotics antifungalmycin B-E (

Language: Английский

Citations

4
Deciphering the role of mitochondria in human fungal drug resistance DOI Creative Commons
Yuanyuan Ma, Yachun Zhou,

Tianyuan Jia

et al.

Mycology&#58 An International Journal on Fungal Biology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 14

Published: March 10, 2025

Language: Английский

Citations

0
Uncovering the role of mitochondrial genome in pathogenicity and drug resistance in pathogenic fungi DOI Creative Commons
Yue Ni, Xindi Gao

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: April 16, 2025

Fungal infections are becoming more prevalent globally, particularly affecting immunocompromised populations, such as people living with HIV, organ transplant recipients and those on immunomodulatory therapy. Globally, approximately 6.55 million affected by invasive fungal annually, leading to serious health consequences death. Mitochondria membrane-bound organelles found in almost all eukaryotic cells play an important role cellular metabolism energy production, including pathogenic fungi. These possess their own genome, the mitochondrial which is usually circular encodes proteins essential for production. Variation evolutionary adaptation within between species' genomes can affect function, consequently production metabolic activity, may contribute pathogenicity drug resistance certain species. This review explores link genome mechanisms of resistance, a particular focus Cryptococcus neoformans Candida albicans. insights deepen our understanding biology provide new avenues developing innovative therapeutic strategies.

Language: Английский

Citations

0
Alternative Oxidase – Aid or obstacle to combat the rise of fungal pathogens? DOI Creative Commons
Elizabeth Edrich, Lucian Duvenage, Campbell W. Gourlay

et al.

Biochimica et Biophysica Acta (BBA) - Bioenergetics, Journal Year: 2024, Volume and Issue: 1865(2), P. 149031 - 149031

Published: Jan. 7, 2024

Fungal pathogens present a growing threat to both humans and global health security alike. Increasing evidence of antifungal resistance in fungal populations that infect plant species has increased reliance on combination therapies shown the need for new therapeutic targets be investigated. Here, we review roles mitochondria respiration pathogenesis discuss role Alternative Oxidase enzyme (Aox) human phytopathogens. exists Aox within mechanisms underpin virulence. also plays important adaptability may prove useful dual targeted fungal-specific approaches. As improved specific mitochondrial inhibitors are under development see this as an emerging target future approaches tackling challenge infection.

Language: Английский

Citations

3
Highly Reactive Group I Introns Ubiquitous in Pathogenic Fungi DOI Creative Commons
Tianshuo Liu, Anna Marie Pyle

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(8), P. 168513 - 168513

Published: March 5, 2024

Systemic fungal infections are a growing public health threat, and yet viable antifungal drug targets limited as fungi share similar proteome with humans. However, features of RNA metabolism the noncoding transcriptomes in distinctive. For example, harbor highly structured elements that humans lack, such self-splicing introns within key housekeeping genes mitochondria. location function these mitochondrial riboregulatory has largely eluded characterization. Here we used an RNA-structure-based bioinformatics pipeline to identify group I interrupting medically relevant fungi, revealing their fixation handful genetic hotspots ubiquitous presence across divergent phylogenies including all highest priority pathogens Candida albicans, auris, Aspergillus fumigatus Cryptococcus neoformans. We then biochemically characterized two representative from C. albicans demonstrating exceptionally efficient splicing catalysis relative previously-characterized introns. Indeed, intron displays extremely rapid catalytic turnover, even at ambient temperatures physiological magnesium ion concentrations. Our results unmask significant new set players pathogenic suggesting promising type target.

Language: Английский

Citations

3
The progress and future of the treatment of Candida albicans infections based on nanotechnology DOI Creative Commons
Yang Gao,

Q. Q. Cao,

Yuyang Xiao

et al.

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Sept. 16, 2024

Systemic infection with Candida albicans poses a significant risk for people weakened immune systems and carries mortality rate of up to 60%. However, current therapeutic options have several limitations, including increasing drug tolerance, notable off-target effects, severe adverse reactions. Over the past four decades, progress in developing drugs treat infections has been sluggish. This comprehensive review addresses limitations existing summarizes efforts made toward redesigning innovating or novel through nanotechnology. The discussion explores potential applications nanomedicine from perspectives: nano-preparations anti-biofilm therapy, innovative formulations "old drugs" targeting cell membrane wall, reverse resistance therapy subcellular organelles, virulence deprivation leveraging unique polymorphism albicans. These approaches are promising address above challenges enhance efficiency development infections. By harnessing nano-preparation technology transform preclinical drugs, targets will be uncovered, providing effective solutions broader horizons improve patient survival rates.

Language: Английский

Citations

3
Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems DOI
Harshini Weerasinghe, Helen Stölting, Adam J. Rose

et al.

Microbiology and Molecular Biology Reviews, Journal Year: 2024, Volume and Issue: 88(3)

Published: Sept. 4, 2024

SUMMARY The ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches their encounter with immune cells. Immune cells require adaptations for producing antimicrobial compounds mounting antifungal inflammation. Infection also triggers systemic changes organ metabolism energy expenditure that range from an enhanced produce robust response reduced as infection progresses, which coincides dysfunction. Competition nutrients between hosts pathogens means successful survival recovery balance elimination the pathogen by systems (resistance), doing so minimal damage tissues organs (tolerance). Here, we discuss our current knowledge pathogen, cell fungal infections, impact disorders, such obesity diabetes. We put forward idea that, while use regulation proliferation responses (i.e., resistance) has been growing over years, need study mechanisms control tolerance pathogens. A comprehensive understanding how resistance interventions may provide insights into therapeutic strategies could be used adjunctly drugs improve patient outcomes.

Language: Английский

Citations

2
Current Perspectives on Antifungal Resistance: Focus on Opportunistic Mycoses DOI Creative Commons
N Muñoz, Carlos Fernando Yauli Flores

Salud Ciencia y Tecnología, Journal Year: 2024, Volume and Issue: 4, P. 1064 - 1064

Published: Jan. 1, 2024

Introduction: opportunistic mycoses, caused by fungi in individuals with compromised immune systems, are on the rise, posing significant challenges healthcare. This article reviews antifungal resistance aim of highlighting its increasing incidence and need for new therapeutic strategies precise diagnostic methods. The necessity standardized laboratory protocols implementation sensitive techniques early detection optimal treatment is emphasized. Methods: a systematic review was conducted using PubMed, Scopus, Google Scholar; search terms Boolean operators such as "(Opportunistic Mycoses) AND (Antifungal Resistance)" "(Antifungals) (Resistance Genes)" were used. Additionally, guidelines established PRISMA statement followed, PICO approach employed. Results: twelve studies evaluated; 58,33 % (n=7) assessed resistance, while 41,67 (n=5) addressed aspects mechanisms action genetics. 66 evaluated Candida spp., 16,7 analyzed Aspergillus making them most studied pathogens. Various genes all studies; moreover, fluconazole found to be antifungal, followed amphotericin B voriconazole. Conclusion: identification development therapies, standardization methods essential mitigate impact public health

Language: Английский

Citations

1
Antifungal activity of bamemacrolactine C against Talaromyces marneffei and its possible mechanisms of action DOI
Cuiping Jiang, Guangfu Feng,

Zhou Wang

et al.

Journal of Applied Microbiology, Journal Year: 2024, Volume and Issue: 135(12)

Published: Dec. 1, 2024

Abstract Aims The present study aims to investigate the in vitro antifungal activity and mechanism of action bamemacrolactine C (BAC), a new 24-membered macrolide compound, against Talaromyces marneffei. Methods results test drug BAC initially demonstrated through paper disk diffusion assay, followed by determination minimum inhibitory concentration value 35.29 μg ml−1 using microdilution. association revealed that combination therapy exhibited additive effects (0.5 < FICI 1.0) when combined with either amphotericin B or fluconazole. A time-growth assay confirmed treatment completely inhibited growth T. marneffei effects. Micromorphological analysis scanning electron microscopy transmission photomicrographs induced morphological damage fungal cells compared control group. Transmembrane protein assays showed significant reduction levels Na+/K+-ATPase (P .05) Ca2+-ATPase .01) Intracellular enzyme significantly decreased ATP, malate dehydrogenase, succinate dehydrogenase content .01). proteomics parallel reaction monitoring (PRM) verification indicated exhibits an downregulating ATP citric acid lyase (ACLY) , potentially affecting tricarboxylic (TCA) cycle. Besides, binding model ACLY also shows good docking score. Conclusions findings suggest marneffei, elucidating its multifaceted involving disruption cell membranes’ integrity inhibition intracellular activities, which modulation TCA cycle may play important role.

Language: Английский

Citations

1