title: Activity of potent and selective host defense peptide mimetics in mouse models of oral candidiasis.
abstract: There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.
authors.affiliation: Public Health Research Institute and Department of Medicine, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Ryan
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, Pennsylvania, USA.
authors.forename: Katie B
authors.initials: KB
authors.lastname: Freeman
authors.affiliation: Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Masso-Silva
authors.affiliation: Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Falkovsky
authors.affiliation: Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
authors.forename: Ashwag
authors.initials: A
authors.lastname: Aloyouny
authors.affiliation: Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Markowitz
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA Medical Service, Louis Stokes Cleveland Department of Veterans Affairs, Cleveland, Ohio, USA.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.affiliation: Department of Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Fatahzadeh
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, Pennsylvania, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Scott
authors.affiliation: Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA gdiamond@dental.ufl.edu.
authors.forename: Gill
authors.initials: G
authors.lastname: Diamond
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002176:Candida albicans / Q000737:chemistry*; D002180:Candidiasis, Oral / Q000382:microbiology*; D002470:Cell Survival; D025141:Drug Resistance, Fungal; D057166:High-Throughput Screening Assays; D025301:Hyphae / Q000737:chemistry; D016867:Immunocompromised Host; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010455:Peptides; D023083:beta-Defensins
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2477-82
references.pmid: 15215097
references.citation: Virulence. 2013 Jul 1;4(5):391-9
references.pmid: 23715031
references.citation: Oral Dis. 2012 Apr;18(3):260-4
references.pmid: 22059932
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):4125-32
references.pmid: 17785509
references.citation: Antimicrob Agents Chemother. 2014;58(4):2006-12
references.pmid: 24419346
references.citation: Curr Opin Gastroenterol. 2006 Jan;22(1):18-23
references.pmid: 16319672
references.citation: Eukaryot Cell. 2007 Oct;6(10):1876-88
references.pmid: 17715369
references.citation: Nat Protoc. 2012 Mar 08;7(4):637-42
references.pmid: 22402633
references.citation: Curr Pharm Des. 2009;15(21):2377-92
references.pmid: 19601838
references.citation: J Med Chem. 2003 Apr 24;46(9):1567-70
references.pmid: 12699374
references.citation: Clin Microbiol Rev. 1999 Oct;12(4):501-17
references.pmid: 10515900
references.citation: PLoS One. 2014 Jan 22;9(1):e85836
references.pmid: 24465737
references.citation: FEMS Microbiol Lett. 1993 Jul 15;111(1):63-7
references.pmid: 8359681
references.citation: J Antimicrob Chemother. 2006 May;57(5):899-907
references.pmid: 16524895
references.citation: Anal Chem. 2009 Oct 15;81(20):8365-72
references.pmid: 19754103
references.citation: PLoS One. 2009;4(4):e5039
references.pmid: 19352427
references.citation: J Prosthodont. 2013 Jan;22(1):13-22
references.pmid: 23107189
references.citation: J Dent Res. 2005 Nov;84(11):966-77
references.pmid: 16246925
references.citation: J Clin Microbiol. 2000 Jun;38(6):2369-73
references.pmid: 10835005
references.citation: Microbiol Immunol. 1996;40(11):821-5
references.pmid: 8985937
references.citation: J Clin Microbiol. 2003 Jan;41(1):506-8
references.pmid: 12517908
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):6968-73
references.pmid: 19359494
references.citation: Infect Immun. 2011 Jun;79(6):2250-6
references.pmid: 21422187
references.citation: Am J Gastroenterol. 1994 Jul;89(7):1062-5
references.pmid: 8017366
references.citation: Cell Host Microbe. 2009 May 8;5(5):487-97
references.pmid: 19454352
references.citation: Clin Microbiol Rev. 2001 Apr;14(2):398-429
references.pmid: 11292645
references.citation: JAMA. 1970 Sep 14;213(11):1859-62
references.pmid: 5468912
references.citation: Postgrad Med J. 2002 Aug;78(922):455-9
references.pmid: 12185216
references.citation: Methods Mol Biol. 2009;552:213-29
references.pmid: 19513652
references.citation: Clin Vaccine Immunol. 2012 Nov;19(11):1784-91
references.pmid: 22956655
references.citation: J Med Vet Mycol. 1992;30 Suppl 1:19-28
references.pmid: 1474444
references.citation: Oral Dis. 2004 Jul;10(4):221-8
references.pmid: 15196144
references.citation: Acc Chem Res. 2010 Jan 19;43(1):30-9
references.pmid: 19813703
references.citation: Clin Microbiol Infect. 2012 Dec;18 Suppl 7:68-77
references.pmid: 23137138
references.citation: J Biol Chem. 1988 Jun 5;263(16):7472-7
references.pmid: 3286634
references.citation: Antimicrob Agents Chemother. 2008 Mar;52(3):937-43
references.pmid: 18180347
references.citation: J Am Chem Soc. 2012 Jul 11;134(27):11088-91
references.pmid: 22697149
references.citation: Antimicrob Agents Chemother. 2011 Nov;55(11):5043-53
references.pmid: 21844313
references.citation: Cancer. 1988 Nov 1;62(9):2042-6
references.pmid: 3167816
references.citation: Antimicrob Agents Chemother. 2003 Aug;47(8):2619-23
references.pmid: 12878528
references.citation: J Antimicrob Chemother. 2006 Nov;58(5):950-9
references.pmid: 17023499
references.citation: Mol Oral Microbiol. 2010 Dec;25(6):418-25
references.pmid: 21040515
references.citation: Infect Immun. 2002 Jun;70(6):3068-72
references.pmid: 12010999
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5449-53
references.pmid: 3299384