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Background A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, Olorofim (formerly F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated.
Methods Sample preparation was based on protein precipi...
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Citations
... By virtue of its novel target enzyme and mechanism of action, olorofim has activity against isolates that are resistant to current treatment options, including several species that can be resistant to all commercially available antifungal drugs such as Scedosporium apiospermum, L. prolificans, Rasamsonia spp., Penicillium spp., and Scopulariopsis spp. (including Scopulariopsis brumptii) [117,151,153,[160][161][162][163][164]. Olorofim also maintains good activity against azole resistant A. fumigatus isolates [151,165], including CYP51A active mutants and hard-to-treat cryptic species of Aspergillus, such as A. nidulans, A. tubingensis, A. lentulus, and A. calidoustus [152,154,166,167]. ...
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
... In vitro studies have shown broad-spectrum activity against filamentous and dimorphic fungi including Aspergillus spp, Histoplasma capsulatum, B dermatitidis, C immitis, Talaromyces (formerly Penicillium) marneffei, and Fusarium spp [128], as well as organisms pan-resistant to clinically available antifungal agents such as Scedosporium apiospermum, L prolificans and Scopulariopsis spp (including Scopulariopsis brumptii) [133][134][135]. It is highly active against all pathogenic Aspergillus spp including wild-type and azole-resistant CYP51A mutant strains, with an MIC of <0.1 µg/mL. ...
The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug-resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, two glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include three fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. Additionally, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising.
The analysis of biosamples, e.g. blood, is a ubiquitous task of proteomics, genomics and biosensing fields, yet it still faces multiple challenges, one of the greatest being the selective separation and detection of target proteins from these complex biosamples. Here, we demonstrate the development of an on-chip light-triggered reusable nanostructured selective and quantitative protein separation and preconcentration platform for the direct analysis of complex biosamples. The on-chip selective separation of required protein analytes from raw biosamples is performed using antibody~photoacid-modified Si nanopillars vertical arrays (SiNPs) of ultra-large binding surface area and enormously high binding affinity, followed by the light-controlled rapid release of the tightly bound target proteins in a controlled liquid media. Two important experimental observations are presented: 1) The first demonstration on the control of biological reaction binding affinity by the nanostructuring of the capturing surface, leading to highly efficient protein collection capabilities, 2) The light-triggered switching of the highly-sticky binding surfaces into highly-reflective non-binding surfaces leading to the rapid and quantitative release of the originally tightly bound protein species. Both of these two novel behaviors were theoretically and experimentally investigated. Importantly, this is the first demonstration of a 3D SiNPs on-chip filter with ultra-large binding surface area and reversible light-controlled quantitative release of adsorbed biomolecules for direct purification of blood samples, able to selectively collect and separate specific low abundant proteins, while easily removing unwanted blood components (proteins, cells) and achieving desalting results, without the requirement of time-consuming centrifugation steps, the use of desalting membranes or affinity columns.
