{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:53:17Z","timestamp":1753890797048,"version":"3.41.2"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Influenza-associated pulmonary aspergillosis is associated with high mortality rates and limited treatment options. The current standard practice involves treating each pathogen separately. However, the use of antifungal drugs can lead to serious side effects, and the presence of triazole-resistant <jats:italic>Aspergillus<\/jats:italic> strains can complicate antifungal therapy. In addition, drug-resistant influenza viruses are becoming an increasing concern in clinics. A drug that affects fungal and viral propagation could overcome these disadvantages. Thus, we conducted a study to examine the antifungal and antiviral properties of ProcCluster\u00ae and procaine hydrochloride (HCl), which are prodrugs derived from the local anesthetic procaine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Conidia of different <jats:italic>A. fumigatus<\/jats:italic> strains, <jats:italic>A. flavus<\/jats:italic> and <jats:italic>A. terreus<\/jats:italic> were treated with the test substances in a human cell-free system and antifungal properties were analyzed either by fluorescence microscopy or absorption measurements. Changes in metabolic activity and intracellular Ca<jats:sup>2+<\/jats:sup> distribution during treatment of <jats:italic>A. fumigatus<\/jats:italic> with ProcCluster\u00ae were observed using fluorescence microscopy. In addition, antifungal and antiviral properties of ProcCluster\u00ae and procaine HCl were investigated during <jats:italic>in vitro<\/jats:italic> coinfection of lung epithelial cells with <jats:italic>A. fumigatus<\/jats:italic> and influenza A viruses (IAV). Analysis was performed by fluorescence microscopy, standard plaque assay and Western blot assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both substances inhibited the growth of the fungus, even when applied after germination or in the presence of purified IAV particles. ProcCluster\u00ae remained effective against triazole-resistant <jats:italic>A. fumigatus<\/jats:italic> strains. However, the addition of CaCl<jats:sub>2<\/jats:sub> reversed the antifungal effect, indicating that ProcCluster\u00ae inhibited fungal growth by disrupting fungal Ca<jats:sup>2+<\/jats:sup> homeostasis. Furthermore, <jats:italic>in vitro<\/jats:italic> studies showed that ProcCluster\u00ae and procaine HCl reduced the pathogen load of IAV and <jats:italic>A. fumigatus<\/jats:italic> during coinfection. Finally, the combination of ProcCluster\u00ae with the antiviral drug favipiravir exhibited increased antipathogenic activity, particularly against IAV replication.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This research highlights ProcCluster\u00ae and procaine HCl as substances with anti-infective properties against various pathogens.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2024.1445428","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T05:10:29Z","timestamp":1728969029000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["ProcCluster\u00ae and procaine hydrochloride inhibit the growth of Aspergillus species and exert antimicrobial properties during coinfection with influenza A viruses and A. fumigatus in vitro"],"prefix":"10.3389","volume":"14","author":[{"given":"Sarah","family":"K\u00f6nig","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josefine","family":"Schroeder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorsten","family":"Heinekamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel A.","family":"Brakhage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"L\u00f6ffler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Engert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Ehrhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofx105","article-title":"A review of clinical influenza A and B infections with reduced susceptibility to both oseltamivir and zanamivir","volume":"4","author":"Abed","year":"2017","journal-title":"Open Forum Infect. 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