{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:27:13Z","timestamp":1785403633941,"version":"3.56.0"},"reference-count":98,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["3021\/20"],"award-info":[{"award-number":["3021\/20"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Invasive fungal infections are associated with high mortality and are increasingly difficult to treat due to a limited antifungal arsenal and the rapid emergence of drug resistance. Novel therapeutic strategies that combine potent antifungal activity, low host toxicity,\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      stability, and a reduced propensity for resistance development are urgently needed. Antimicrobial peptides (AMPs) stand out as a promising class of compounds to combat antimicrobial resistance. Leveraging the unique properties of AMPs, we previously developed a novel approach to synthesize random peptide mixtures (RPMs) with robust bactericidal activity against drug-resistant bacteria. Here, we evaluate the antifungal potential of RPMs and demonstrate species-dependent, broad-spectrum activity of FK20 (L-phenylalanine\u2013L-lysine, 20-mer) against major human fungal pathogens, including\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      spp.,\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      , with particularly high potency against the multidrug-resistant pathogen\n                      <jats:italic toggle=\"yes\">Candida auris<\/jats:italic>\n                      . Mechanistic analyses revealed rapid membrane and cell wall disruption accompanied by intracellular penetration, consistent with membrane-active antifungal activity. Importantly, experimental evolution assays demonstrated a markedly reduced capacity for resistance development in\n                      <jats:italic toggle=\"yes\">C. auris<\/jats:italic>\n                      . FK20 inhibited biofilm formation and displayed substantial activity against mature, pre-formed biofilms, both alone and synergistically in combination with caspofungin. Finally, FK20 showed significant therapeutic efficacy in a murine model of systemic candidiasis. Collectively, these findings establish RPMs as a versatile antifungal platform with broad-spectrum activity, biofilm efficacy, and a low resistance footprint, highlighting their promise as a novel therapeutic strategy against drug-resistant fungal infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The rising prevalence of invasive fungal infections, particularly among immunocompromised individuals, has become a critical public health concern. However, antifungal drug development has not kept pace with this growing need, and treatment options remain limited to a small number of drug classes. The emergence of multidrug-resistant fungal pathogens, such as\n                      <jats:italic toggle=\"yes\">Candida auris<\/jats:italic>\n                      , further exacerbates this crisis by reducing the efficacy of existing therapeutics and increasing the risk of treatment failure. In this study, we evaluate the antifungal potential of FK20, a random peptide mixture (RPM) composed of L-phenylalanine and L-lysine. FK20 displays potent activity against\n                      <jats:italic toggle=\"yes\">C. auris<\/jats:italic>\n                      and other clinically relevant\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      species, impairs biofilm formation, and exhibits synergy with caspofungin. Importantly, FK20 limits the emergence of resistance and demonstrates therapeutic efficacy in a murine model of systemic candidiasis. These findings establish RPMs as a promising new class of antifungals with broad-spectrum activity and clinical potential against drug-resistant fungal infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00400-26","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T13:00:48Z","timestamp":1776171648000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing random peptide mixtures to combat multidrug-resistant fungal infections"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0621-4889","authenticated-orcid":false,"given":"John","family":"Adeoye","sequence":"first","affiliation":[{"name":"Koret School of Veterinary Medicine, Faculty of Agriculture, The Hebrew University","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Belo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01rd8n845","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biochemistry, Food Science and Nutrition, The Robert H. 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