{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:52:08Z","timestamp":1790815928988,"version":"4.1.0"},"update-to":[{"DOI":"10.12688\/f1000research.28327.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000}}],"reference-count":94,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Henry Schueller Foundation"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. \u00a0The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics.\u00a0 This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim.\u00a0 We discuss three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic 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Colley","year":"2019","journal-title":"Sci Rep."},{"key":"ref-81","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00124-17","article-title":"In vivo biomarker analysis of the effects of intranasally dosed PC945, a novel antifungal triazole, on Aspergillus fumigatus infection in immunocompromised mice.","volume":"61","author":"G Kimura","year":"2017","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-82","doi-asserted-by":"publisher","first-page":"1505-1506","DOI":"10.1016\/j.healun.2020.09.015","article-title":"Successful salvage therapy for fungal bronchial anastomotic infection after -lung transplantation with an inhaled triazole anti-fungal PC945.","volume":"39","author":"N Pagani","year":"2020","journal-title":"J Hear Lung Transplant."},{"key":"ref-83","doi-asserted-by":"publisher","first-page":"12809-12814","DOI":"10.1073\/pnas.1608304113","article-title":"F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase.","volume":"113","author":"J Oliver","year":"2016","journal-title":"Proc Natl Acad Sci U S A."},{"key":"ref-84","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00999-18","article-title":"The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis.","volume":"62","author":"N Wiederhold","year":"2018","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-85","doi-asserted-by":"publisher","first-page":"2548-2552","DOI":"10.1093\/jac\/dkx177","article-title":"In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates.","volume":"72","author":"J Buil","year":"2017","journal-title":"J Antimicrob Chemother."},{"key":"ref-86","doi-asserted-by":"publisher","first-page":"1977-1980","DOI":"10.1093\/jac\/dkx065","article-title":"Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro activity against Scedosporium species and Lomentospora 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Jorgensen","year":"2018","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-90","doi-asserted-by":"publisher","first-page":"106105","DOI":"10.1016\/j.ijantimicag.2020.106105","article-title":"In vitro activity of olorofim (F901318) against fungi of the genus, Scedosporium and Rasamsonia as well as against Lomentospora prolificans, Exophiala dermatitidis and azole-resistant Aspergillus fumigatus.","volume":"56","author":"L Kirchhoff","year":"2020","journal-title":"Int J Antimicrob Agents."},{"key":"ref-91","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01157-17","article-title":"Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease.","volume":"8","author":"W Hope","year":"2017","journal-title":"mBio."},{"key":"ref-92","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00231-18","article-title":"Effect of the Novel Antifungal Drug F901318 (Olorofim) on Growth and Viability of Aspergillus fumigatus.","volume":"62","author":"S du Pr\u00e9","year":"2018","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-93","first-page":"P1710","article-title":"Multiple Dose Pharmacokinetics of an Immediate-Release Tablet Formulation of F901318 in Healthy Male and Female Subjects","author":"T Kennedy","year":"2017","journal-title":"European Congress of Clinical Microbiology and Infectious Diseases."},{"key":"ref-94","first-page":"P1737","article-title":"An open-label study in healthy volunteers to evaluate the potential for cytochrome P450 3A4 inhibition by F901318 using oral midazolam as a probe","author":"T Kennedy","year":"2017","journal-title":"European Congress of Clinical Microbiology and Infectious Diseases."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/10-507\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-507\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-507\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T03:55:20Z","timestamp":1642996520000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/10-507\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":94,"URL":"https:\/\/doi.org\/10.12688\/f1000research.28327.2","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.119851.r119566","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.119851.r119566","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/10-507\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.31334.r89343, Charalampos Antachopoulos, Third Department of Pediatrics, Faculty of Medicine,  School of Health Sciences, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece, 23 Jul 2021, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-507\/v1#referee-response-89343","order":0,"name":"referee-response-89343","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Samantha Jacobs<\/b>; \n<i>Posted: 27 Dec 2021<\/i>; \n<b>Response to Reviewer #1 Comments<\/b> \n<b>12.27.2021<\/b>  This is a well-written and comprehensive paper summarizing recent data on novel antifungal agents in clinical development. Table 1 is very helpful. I have only few minor comments:  1.&nbsp;Abstract: consider change \u201cwe examine\u201d to: \u201cwe review \/ present \/ discuss\u201d. \n<b>Author response<\/b>: We have changed the wording to \u201cWe discuss\u2026\u201d &nbsp; 2. Fosmanogepix: please provide more specific&nbsp;\n<i>in vitro&nbsp;<\/i>data on species (rather than genera) susceptibility for&nbsp;\n<i>Aspergillus&nbsp;<\/i>spp,&nbsp;\n<i>Fusarium<\/i>&nbsp;spp and&nbsp;\n<i>Scedosporium<\/i>&nbsp;spp. \n<b>Author response<\/b>: We have specified the \n<i>in vitro<\/i> activity of fosmanogepix to the species level including representative MEC values. &nbsp; \n<i>3. In vitro<\/i>&nbsp;antifungal activity of fosmanogepix: it should be mentioned that MEC rather than MIC is determined for assessment of activity against molds. \n<b>Author response<\/b>: We have added a line noting this distinction.  4. \u201cFosmanogepix also has activity against fungi in the order Mucorales (MIC ranges of 1 to 8 &micro;g\/mL)\u201d: please provide reference for this statement; is the term MIC correct or should it be replaced by MEC?\n<b>Author response<\/b>: We have added the reference for this statement (reference #2).&nbsp; Indeed, the manuscript, published in 2011, used MIC rather the MEC determination for activity of fosmanogepix against \n<i>R. oryzae<\/i> and \n<i>R. microsporus<\/i>. We have also added another reference that reports MEC values (reference #3).  5. \u201cIbrexafungerp has fungistatic activity against&nbsp;\n<i>Aspergillus<\/i>&nbsp;species (MIC range &lt;0.06 &micro;g\/mL to 32 &micro;g\/mL\u2026)\u201d: in the reference cited by the authors (ref. 25, Ghannoum et al, AAC 2018), ibrexafungerp&nbsp;\n<i>in vitro&nbsp;<\/i>activity against&nbsp;\n<i>Aspergillus<\/i>&nbsp;had been determined using both MEC and MIC; the MIC values tended to be 8-fold higher than correspondent MEC values. Please modify the text accordingly. \n<b>Author response<\/b>: Thank you for your comment. We have modified the text to report the MEC rather than MIC determinations for ibrexafungerp against \n<i>Aspergillus<\/i> species. &nbsp; 6. Are there data on the&nbsp;\n<i>in vitro<\/i>&nbsp;activity of ibrexafungerp and rezafungin against&nbsp;\n<i>Candida parapsilosis<\/i>&nbsp;in comparison with other&nbsp;\n<i>Candida<\/i>&nbsp;species? \n<b>Author response:<\/b> Thank you for your question.&nbsp; The \n<i>in vitro<\/i> activity of ibrexafungerp against \n<i>C. parapsilosis<\/i> is comparable or more potent than that of echinocandins. The MICs against \n<i>C. parapsilosis<\/i> are generally similar to those of other \n<i>Candida<\/i> species. For rezafungin, the \n<i>in vitro<\/i> activity against \n<i>C. parapsilosis <\/i>is less potent than against other common \n<i>Candida<\/i> species causing disease. These data are added to the text. &nbsp; 7. What is the published evidence for PK\/PD indices associated with therapeutic outcome for each one of the novel antifungal agents presented in this paper? \n<b>Author response<\/b>:&nbsp; For fosmanogepix, ibrexafungerp, rezafungin, and olorofim, we have included the key PK\/PD indices associated with therapeutic outcome in experimental animal models as there are insufficient clinical data to determine this information.&nbsp; We have also created an additional table (Table 2) to highlight this information.  8.&nbsp;Conclusion:&nbsp;the content of the conclusion paragraph would fit more for an introduction rather than a wrap-up of the main findings. I suggest to significantly modify this section, in order to briefly mention the novel agents in clinical development and their selective advantages compared to our current antifungal armamentarium. \n<b>Author response<\/b>:&nbsp; We have modified the conclusion as suggested by the reviewer to summarize and highlight the advantages of the most promising investigational agents discussed in the manuscript.","URL":"https:\/\/f1000research.com\/articles\/10-507\/v2#referee-comment-7635","order":1,"name":"referee-comment-7635","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.119851.r119566, Shahram Mahmoudi, Department of Parasitology and Mycology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran, 24 Jan 2022, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/10-507\/v2#referee-response-119566","order":2,"name":"referee-response-119566","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work is supported by the Henry Schueller Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}