Hope on the Horizon: Novel Fungal Treatments in Development

Rauseo, Adriana M; Coler‐Reilly, Ariella; Larson, Lindsey; Spec, Andrej

doi:10.1093/ofid/ofaa016

Cited by 159 publications

(148 citation statements)

References 148 publications

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“…New antifungal agents with novel modes of action are in the pipeline so as to address the problem of antifungal resistance, which threatens the effectiveness of the few agents currently being used to treat invasive fungal disease [ 65 ]. Clinical trials are ongoing for three new antifungal agents, namely, ibrexafungerp (NCT03672292) [ 66 ], olorofim (NCT03583164) [ 67 ], and fosmanogepix (NCT04240886) [ 68 ].…”

Section: Antifungal Treatment Strategies For Capamentioning

confidence: 99%

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

Mohamed

Rogers

Talento

2020

JoF

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Aspergillus co-infection in patients with severe coronavirus disease 2019 (COVID-19) pneumonia, leading to acute respiratory distress syndrome, has recently been reported. To date, 38 cases have been reported, with other cases most likely undiagnosed mainly due to a lack of clinical awareness and diagnostic screening. Importantly, there is currently no agreed case definition of COVID-19 associated invasive pulmonary aspergillosis (CAPA) that could aid in the early detection of this co-infection. Additionally, with the global emergence of triazole resistance, we emphasize the importance of antifungal susceptibility testing in order to ensure appropriate antifungal therapy. Herein is a review of 38 published CAPA cases, which highlights the diagnostic and therapeutic challenges posed by this novel fungal co-infection.

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Section: Antifungal Treatment Strategies For Capamentioning

confidence: 99%

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

Mohamed

Rogers

Talento

2020

JoF

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“…Only four classes of antifungal drugs are currently available on the market [3]. Olorofim (formerly known as F901318) is a novel antifungal belonging to a new class of drugs, called the orotomides, that is currently in phase two of clinical development [4][5][6]. Olorofim selectively inhibits the de novo pyrimidine biosynthesis of filamentous fungi by targeting dihydroorotate dehydrogenase (DHODH) [7].…”

Section: Introductionmentioning

confidence: 99%

The Dynamic Influence of Olorofim (F901318) on the Cell Morphology and Organization of Living Cells of Aspergillus fumigatus

Pré

Birch²,

Law³

et al. 2020

JoF

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The first characterized antifungal in the orotomide class is olorofim. It targets the de novo pyrimidine biosynthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH). The pyrimidines uracil, thymine and cytosine are the building blocks of DNA and RNA; thus, inhibition of their synthesis is likely to have multiple effects, including affecting cell cycle regulation and protein synthesis. Additionally, uridine-5′-triphosphate (UTP) is required for the formation of uridine-diphosphate glucose (UDP-glucose), which is an important precursor for several cell wall components. In this study, the dynamic effects of olorofim treatment on the morphology and organization of Aspergillus fumigatus hyphae were analyzed microscopically using confocal live-cell imaging. Treatment with olorofim led to increased chitin content in the cell wall, increased septation, enlargement of vacuoles and inhibition of mitosis. Furthermore, vesicle-like structures, which could not be stained or visualized with a range of membrane- or vacuole-selective dyes, were found in treated hyphae. A colocalization study of DHODH and MitoTracker Red FM confirmed for the first time that A. fumigatus DHODH is localized in the mitochondria. Overall, olorofim treatment was found to significantly influence the dynamic structure and organization of A. fumigatus hyphae.

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“…A number of novel antifungal agents (e.g., amphotericin B cochleates, ibrexafungerp, nikkomycin Z, olorofim, rezafungin) are in various stages of development [157][158][159][160][161][162]. Their role, if any, in the treatment of chronic pulmonary aspergillosis is yet to be established.…”

Section: Novel Antifungal Therapiesmentioning

confidence: 99%

A Collaborative Tale of Diagnosing and Treating Chronic Pulmonary Aspergillosis, from the Perspectives of Clinical Microbiologists, Surgical Pathologists, and Infectious Disease Clinicians

Larkin

Multani

Beaird

et al. 2020

JoF

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Chronic pulmonary aspergillosis (CPA) refers to a spectrum of Aspergillus-mediated disease that is associated with high morbidity and mortality, with its true prevalence vastly underestimated. The diagnosis of CPA includes characteristic radiographical findings in conjunction with persistent and systemic symptoms present for at least three months, and evidence of Aspergillus infection. Traditionally, Aspergillus infection has been confirmed through histopathology and microbiological studies, including fungal culture and serology, but these methodologies have limitations that are discussed in this review. The treatment of CPA requires an individualized approach and consideration of both medical and surgical options. Most Aspergillus species are considered susceptible to mold-active triazoles, echinocandins, and amphotericin B; however, antifungal resistance is emerging and well documented, demonstrating the need for novel therapies and antifungal susceptibility testing that correlates with clinical response. Here, we describe the clinical presentation, diagnosis, and treatment of CPA, with an emphasis on the strengths and pitfalls of diagnostic and treatment approaches, as well as future directions, including whole genome sequencing and metagenomic sequencing. The advancement of molecular technology enables rapid and precise species level identification, and the determination of molecular mechanisms of resistance, bridging the clinical infectious disease, anatomical pathology, microbiology, and molecular biology disciplines.

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Hope on the Horizon: Novel Fungal Treatments in Development

Cited by 159 publications

References 148 publications

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

The Dynamic Influence of Olorofim (F901318) on the Cell Morphology and Organization of Living Cells of Aspergillus fumigatus

A Collaborative Tale of Diagnosing and Treating Chronic Pulmonary Aspergillosis, from the Perspectives of Clinical Microbiologists, Surgical Pathologists, and Infectious Disease Clinicians

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