Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease

Clinical Microbiology Reviews, Journal Year: 2024, Volume and Issue: 37(2)

Published: April 11, 2024

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, their utility efficacy in antifungal treatment limited one or more of innate acquired resistance some fungi, poor penetration into "sequestered" sites, agent-specific side effect which require frequent patient reassessment monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, fungicidal mechanism(s) urgently needed. Here, we provide comprehensive review agents, both improved known mechanisms actions new currently clinical development for treating invasive yeast, mold (filamentous fungi),

Language: Английский

---

What Is New in Pulmonary Mucormycosis?

Journal of Fungi, Journal Year: 2023, Volume and Issue: 9(3), P. 307 - 307

Published: Feb. 28, 2023

Mucormycosis is a rare but life-threatening fungal infection due to molds of the order Mucorales. The incidence has been increasing over recent decades. Worldwide, pulmonary mucormycosis (PM) presents in lungs, which are third main location for after rhino-orbito-cerebral (ROC) areas and skin. risk factors PM include hematological malignancies solid organ transplantation, whereas ROC infections classically favored by diabetes mellitus. differences between locations possibly explained activation different mammalian receptors—GRP78 nasal epithelial cells integrin β1 alveolar cells—in response Alveolar macrophages neutrophils play key role host defense against diagnosis relies on CT scans, cultures, PCR tests, histology. reversed halo sign an early, very suggestive, neutropenic patients. Recently, serum test showed encouraging performance follow-up mucormycosis. Liposomal amphotericin B drug choice first-line therapy, together with correction underlying disease surgery when feasible. After stable or partial response, step-down treatment includes oral isavuconazole posaconazole delayed release tablets until complete achieved. Secondary prophylaxis should be discussed there any relapse, such as persistence neutropenia prolonged use high-dose immunosuppressive therapy. Despite these novelties, mortality rate from remains higher than 50%. Therefore, future research must define place combination therapy adjunctive treatments, while development new treatments necessary.

Language: Английский

---

Novel Strategies for Preventing Fungal Infections—Outline

Pathogens, Journal Year: 2025, Volume and Issue: 14(2), P. 126 - 126

Published: Feb. 1, 2025

Fungal infections are a significant global health challenge, causing approximately 3.8 million deaths annually, with immunocompromised populations particularly at risk. Traditional antifungal therapies, including azoles, echinocandins, and polyenes, face limitations due to rising resistance, toxicity, inadequate treatment options. This review explores innovative strategies for preventing managing fungal infections, such as vaccines, peptides, nanotechnology, probiotics, immunotherapy. Vaccines offer promising avenues long-term protection, despite difficulties in their development complexity immune evasion mechanisms. Antifungal peptides provide novel class of agents broad-spectrum activity reduced resistance risk, whilst nanotechnology enables targeted, effective drug delivery systems. Probiotics show potential vulvovaginal candidiasis, by maintaining microbial balance. Immunotherapy leverages system modulation enhance defenses, omics technologies deliver comprehensive insights into biology, paving the way therapeutic vaccine targets. While these approaches hold immense promise, challenges cost, accessibility, translational barriers remain. A coordinated effort among researchers, clinicians, policymakers is critical advancing addressing burden effectively.

Language: Английский

---

Recent developments in Aspergillus fumigatus research: diversity, drugs, and disease

Microbiology and Molecular Biology Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

SUMMARY Advances in modern medical therapies for many previously intractable human diseases have improved patient outcomes. However, successful disease treatment outcomes are often prevented due to invasive fungal infections caused by the environmental mold Aspergillus fumigatus . As contemporary antifungal not experienced same robust advances as other therapies, defining mechanisms of A. initiation and progression remains a critical research priority. To this end, World Health Organization recently identified priority pathogen Centers Disease Control has highlighted emergence triazole-resistant isolates. The expansion diversity host populations susceptible aspergillosis complex dynamic genotypic phenotypic call reinvigorated assessment pathobiological drug-susceptibility mechanisms. Here, we summarize recent advancements field discuss challenges our understanding heterogeneity its pathogenesis diverse populations.

Language: Английский

---

Intestinal fungal-host interactions in promoting and maintaining health

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(10), P. 1668 - 1680

Published: Oct. 1, 2024

The resident microbiota are a key component of healthy organism. vast majority microbiome studies have focused on bacterial members, which constitute significant portion microbial biomass. Recent demonstrated how the fungal microbiota, or mycobiome, influences mammalian biology despite its low abundance compared to other microbes. Fungi known for their pathogenic potential, yet fungi also prominent colonizers in states, highlighting duality. We summarize characteristics that define gut mycobiome across life, factors can impact composition, and identify mechanisms confer health benefits. goal this review is synthesize our knowledge regarding composition function with view inspiring future therapeutic advances.

Language: Английский

---

Construction and Evaluation of Pharmacophore Models: Guide and Design of Novel Ido Inhibitors

Published: Jan. 1, 2025

Indoleamine 2,3-dioxygenase (IDO), as a crucial immunomodulatory target, can play pivotal role in regulating immune function. In this study, the ligand-based pharmacophore model (HDAA) and receptor-based (HHDA) were respectively constructed, which could comprehensively reflect spatial distribution characteristics of core groups IDO inhibitors. Subsequently, these models utilized to guide design novel inhibitor through skeleton combination pathway. The corresponding molecular structures synthesized, their biological activity was evaluated. Notably, compound 7b demonstrated highly effective inhibitory ability achieve body's activation vivo. summary, study not only constructed rational docking but also guided development skeletons, offering promising approach achieving activation.

Language: Английский

---

American Society of Transplantation and Cellular Therapy Series: #8- Management and Prevention of Non-Aspergillus Molds in Hematopoietic Cell Transplantation Recipients

Transplantation and Cellular Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

---

Immunotherapy with nebulized pattern recognition receptor agonists restores severe immune paralysis and improves outcomes in mice with influenza-associated pulmonary aspergillosis

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

ABSTRACT Influenza-associated pulmonary aspergillosis (IAPA) is a potentially deadly superinfection in patients with influenza pneumonia, especially those severe disease, underlying immunosuppression, corticosteroid therapy, or requiring intensive care support. Given the high mortality of IAPA, adjunct immunomodulatory strategies remain critical unmet need. Previously, desensitization pattern recognition pathways has been described as hallmark IAPA pathogenesis and predictor patients. Therefore, we studied impact nebulized Toll-like receptor 2/6/9 agonists Pam2 CSK4 (Pam2) CpG oligodeoxynucleotides (ODNs) on infection outcomes immunopathology corticosteroid-immunosuppressed murine model. Mice receiving mock therapy showed rapidly progressing disease paralyzed immune response to secondary Aspergillus fumigatus infection. Nebulized Pam2ODN was well tolerated significantly prolonged event-free survival. Specifically, dual-dose before after A. led 81% survival full recovery all survivors. Additionally, transcriptional analysis lung tissue homogenates revealed induction signaling several key effector cytokine therapy. Moreover, flow cytometric analyses suggested increased frequencies macrophages, natural killer cells, T cells lungs Pam2ODN-treated mice. Collectively, treatment strongly improved morbidity alleviated antifungal immunity an otherwise lethal These findings suggest that might be promising candidate for locally delivered improve virus-associated mold infections such IAPA. IMPORTANCE The COVID-19 pandemic highlighted significant healthcare burden, morbidity, caused by fungal pneumonias. heightened prevalence viral pneumonias, influenza, poor immunotherapies are needed prevent treat infections. We herein demonstrate severely mouse model influenza-associated (IAPA), partially due dysregulated pathogen-sensing pathways. To overcome paralysis progression, used dyad immunomodulators (Toll-like agonists). immunotherapy compared mature mononuclear phagocytes lung, stimulated antimicrobial signaling. this proof-of-concept study demonstrates feasibility efficacy alleviate virus-induced dysregulation post-viral pneumonias

Language: Английский

---

Advancing Precision Medicine: Uncovering Biomarkers and Strategies to Mitigate Immune-Related Adverse Events in Immune Checkpoint Inhibitors Therapy

Toxicology Reports, Journal Year: 2025, Volume and Issue: unknown, P. 102035 - 102035

Published: April 1, 2025

Language: Английский

---

Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy

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

Published: April 29, 2025

Sepsis, a life-threatening organ dysfunction resulting from dysregulated host response to infection, initiates complex immune that varies over time, characterized by sustained excessive inflammation and immunosuppression. Sepsis-induced immunosuppression is now recognized as major cause of septic death, identifying effective strategies counteract it poses significant challenge. This results the disruption homeostasis, abnormal death effector cells, hyperproliferation suppressor release anti-inflammatory cytokines, expression checkpoints. Preclinical studies targeting immunosuppression, particularly with checkpoint inhibitors, have shown promise in reversing immunocyte dysfunctions establishing resistance pathogens. Here, our review highlights mechanisms sepsis-induced current diagnostic biomarkers, well immune-enhancing evaluated patients therapeutics under investigation.

Language: Английский

---