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.

[1]  Dan Yang,et al.  In Vitro and In Vivo Activity of a Novel Antifungal Small Molecule against Candida Infections , 2014, PloS one.

[2]  J. Guarro,et al.  Multilaboratory Study of Epidemiological Cutoff Values for Detection of Resistance in Eight Candida Species to Fluconazole, Posaconazole, and Voriconazole , 2014, Antimicrobial Agents and Chemotherapy.

[3]  J. C. Junqueira,et al.  Recent mouse and rat methods for the study of experimental oral candidiasis , 2013, Virulence.

[4]  T. Calandra,et al.  ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS. , 2012, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[5]  G. Tew,et al.  Identification of Synthetic Host Defense Peptide Mimics That Exert Dual Antimicrobial and Anti-Inflammatory Activities , 2012, Clinical and Vaccine Immunology.

[6]  G. Tew,et al.  Synthetic mimics of antimicrobial peptides with immunomodulatory responses. , 2012, Journal of the American Chemical Society.

[7]  C. R. Paula,et al.  Treatment with probiotics in experimental oral colonization by Candida albicans in murine model (DBA/2). , 2012, Oral diseases.

[8]  S. Filler,et al.  Mouse model of oropharyngeal candidiasis , 2012, Nature Protocols.

[9]  J. Pemán,et al.  Antifungal Susceptibility Testing of Filamentous Fungi , 2012, Current Fungal Infection Reports.

[10]  W. DeGrado,et al.  Antibacterial Mechanism of Action of Arylamide Foldamers , 2011, Antimicrobial Agents and Chemotherapy.

[11]  Ozlem Yilmaz,et al.  Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells , 2011, Infection and Immunity.

[12]  G. Diamond,et al.  Activity of antimicrobial peptide mimetics in the oral cavity: I. Activity against biofilms of Candida albicans. , 2010, Molecular oral microbiology.

[13]  GREGORY N. TEW,et al.  De novo design of antimicrobial polymers, foldamers, and small molecules: from discovery to practical applications. , 2010, Accounts of chemical research.

[14]  G. Tew,et al.  Dependence of antimicrobial selectivity and potency on oligomer structure investigated using substrate supported lipid bilayers and sum frequency generation vibrational spectroscopy. , 2009, Analytical chemistry.

[15]  Aaron Weinberg,et al.  The roles of antimicrobial peptides in innate host defense. , 2009, Current pharmaceutical design.

[16]  K. Fitzgerald,et al.  An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. , 2009, Cell host & microbe.

[17]  W. DeGrado,et al.  De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers , 2009, Proceedings of the National Academy of Sciences.

[18]  B. Hube,et al.  A Novel Immune Evasion Strategy of Candida albicans: Proteolytic Cleavage of a Salivary Antimicrobial Peptide , 2009, PloS one.

[19]  W. Couet,et al.  Mechanism-Based Pharmacokinetic-Pharmacodynamic Models of In Vitro Fungistatic and Fungicidal Effects against Candida albicans , 2008, Antimicrobial Agents and Chemotherapy.

[20]  G. Tew,et al.  Activity of an Antimicrobial Peptide Mimetic against Planktonic and Biofilm Cultures of Oral Pathogens , 2007, Antimicrobial Agents and Chemotherapy.

[21]  S. Vylkova,et al.  Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway , 2007, Eukaryotic Cell.

[22]  M. Benincasa,et al.  Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts. , 2006, The Journal of antimicrobial chemotherapy.

[23]  C. Deber,et al.  Activity of novel non-amphipathic cationic antimicrobial peptides against Candida species. , 2006, The Journal of antimicrobial chemotherapy.

[24]  L. Samaranayake,et al.  Fungicidal effect of three new synthetic cationic peptides against Candida albicans. , 2004, Oral diseases.

[25]  J. Pemán,et al.  Patterns of Amphotericin B Killing Kinetics against Seven Candida Species , 2004, Antimicrobial Agents and Chemotherapy.

[26]  G. Forrest.  Gastrointestinal infections in immunocompromised hosts , 2004, Current opinion in gastroenterology.

[27]  S. Teraguchi,et al.  Oral Lactoferrin Treatment of Experimental Oral Candidiasis in Mice , 2003, Antimicrobial Agents and Chemotherapy.

[28]  J. Svendsen,et al.  The pharmacophore of short cationic antibacterial peptides. , 2003, Journal of medicinal chemistry.

[29]  M. Ghannoum,et al.  Uses and Limitations of the XTT Assay in Studies of Candida Growth and Metabolism , 2003, Journal of Clinical Microbiology.

[30]  James M. Wilson,et al.  β-Defensin 1 Contributes to Pulmonary Innate Immunity in Mice , 2002, Infection and Immunity.

[31]  L. Samaranayake,et al.  Experimental Oral Candidiasis in Animal Models , 2001, Clinical Microbiology Reviews.

[32]  S. Piscitelli,et al.  Correlation between In Vitro and In Vivo Antifungal Activities in Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis , 2000, Journal of Clinical Microbiology.

[33]  M. Ghannoum,et al.  Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance , 1999, Clinical Microbiology Reviews.

[34]  S. Abe,et al.  Cooperative Anti‐Candida Effects of Lactoferrin or Its Peptides in Combination with Azole Antifungal Agents , 1996, Microbiology and immunology.

[35]  V. Jha,et al.  Esophageal candidiasis after renal transplantation: comparative study in patients on different immunosuppressive protocols. , 1994, The American journal of gastroenterology.

[36]  P. Sullivan,et al.  Expression of the exoglucanase gene in yeast and hyphal forms of Candida albicans. , 1993, FEMS microbiology letters.

[37]  J. Carpenter,et al.  The pathogenesis and clinical significance of cytologically detectable oral Candida in acute leukemia , 1988, Cancer.

[38]  M. Zasloff,et al.  Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Levitz,et al.  Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. , 1988, The Journal of biological chemistry.

[40]  E. Bruck,et al.  National Committee for Clinical Laboratory Standards. , 1980, Pediatrics.

[41]  L. Montes,et al.  Oral Candidiasis , 1978, Journal of cutaneous pathology.

[42]  D. Sheft,et al.  Esophageal moniliasis. The spectrum of the disease. , 1970, JAMA.

[43]  J. Preisser,et al.  Clinical and histological findings of denture stomatitis as related to intraoral colonization patterns of Candida albicans, salivary flow, and dry mouth. , 2013, Journal of prosthodontics : official journal of the American College of Prosthodontists.

[44]  S. Dowell,et al.  Yeast assays for G protein-coupled receptors. , 2009, Methods in molecular biology.

[45]  Clinical,et al.  Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard , 2008 .

[46]  A. Dongari-Bagtzoglou,et al.  The Host Cytokine Responses and Protective Immunity in Oropharyngeal Candidiasis , 2005, Journal of dental research.

[47]  J. Graybill,et al.  Fungal infections in AIDS patients. , 1992, Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology.