Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism

Menzel, Lorenzo P.; Chowdhury, Hossain Mobaswar; Masso-Silva, Jorge A; Ruddick, William; Falkovsky, Klaudia; Vorona, Rafael; Malsbary, Andrew; Cherabuddi, Kartikeya; Ryan, Lisa K.; DiFranco, Kristina M.; Brice, David C.; Costanzo, Michael J.; Weaver, Damian G.; Freeman, Katie B.; Scott, Richard W.; Diamond, Gill

doi:10.1038/s41598-017-04462-6

Cited by 34 publications

(33 citation statements)

References 47 publications

(59 reference statements)

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“…While LL-37 exerts its antiviral activity via a direct effect on the virion in the case of this paper and others, cathelicidins in general (He et al, 2018) and LL-37 specifically (Barlow et al, 2014a) have also been shown to enhance other methods of innate antiviral immunity, namely interferon expression. Current work in endogenous antimicrobial peptide expression (Dhawan et al, 2015; Klein-Patel et al, 2006; Rivas-Santiago et al, 2005; Ryan et al, 2011; Ryan and Diamond, 2017) and small molecule mimetics of antimicrobial peptides (Beckloff et al, 2007; Menzel et al, 2017; Ryan et al, 2014) would potentially serve as methods to prevent not only KSHV infection, but also other viral infections of the oral cavity.…”

Section: Discussionmentioning

confidence: 99%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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Oral epithelial cells (OECs) represent the first line of defense against viruses that are spread via saliva, including Kaposi's sarcoma-associated herpesvirus (KSHV). Infection of humans by KSHV and viral pathogenesis begins by infecting OECs. One method OECs use to limit viral infections in the oral cavity is the production of antimicrobial peptides (AMPs), or host defense peptides (HDPs). However, no studies have investigated the antiviral activities of any HDP against KSHV. The goal of this study was to determine the antiviral activity of one HDP, LL-37, against KSHV in the context of infecting OECs. Our results show that LL-37 significantly decreased KSHV's ability to infect OECs in both a structure- and dose-dependent manner. However, this activity does not stem from affecting OECs, but instead the virions themselves. We found that LL-37 exerts its antiviral activity against KSHV by disrupting the viral envelope, which can inhibit viral entry into OECs. Our data suggest that LL-37 exhibits a marked antiviral activity against KSHV during infection of oral epithelial cells, which can play an important role in host defense against oral KSHV infection. Thus, we propose that inducing LL-37 expression endogenously in oral epithelial cells, or potentially introducing as a therapy, may help restrict oral KSHV infection and ultimately KSHV-associated diseases.

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Section: Discussionmentioning

confidence: 99%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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“…Trichophyton mentagrophytes and T. rubrum microconidia were incubated with peptides for 48 hours in the same conditions described above (Antifungal and mtt assays section). After, peptide‐ and control‐treated microconidia were incubated with 1 µmol/L of propidium iodide (PI) for 30 minutes at 37ºC in the dark, under moderate agitation, according to Menzel et al 18 Then, the cells were washed with 0.15 mol/L of NaCl three times, centrifuged at 3000 g for 5 minutes at 22°C (Mikro 200R centrifuge, Hettich) and observed under a fluorescent microscope (Olympus System BX 60) with an excitation wavelength of 490 nm and an emission wavelength of 520 nm.…”

Section: Methodsmentioning

confidence: 99%

Antidermatophytic activity of synthetic peptides: Action mechanisms and clinical application as adjuvants to enhance the activity and decrease the toxicity of Griseofulvin

Souza

Lima

Freitas

et al. 2020

Mycoses

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Background Dermatophytes belonging to the Trichophyton genus are important human pathogens, but they have developed resistance to griseofulvin, the most common antifungal drug used to treat dermatophytosis. Objective This study was aimed to evaluate the antidermatophytic activity of synthetic peptides, as well as mechanisms of action and synergistic effect with griseofulvin. Methods Scanning electron microscopy (SEM), atomic force microscopy (AFM) and fluorescence microscopy (FM) were employed to understand the activity and the mechanism of action of peptides. Results Here we report that synthetic peptides at 50 μg/mL, a concentration 20‐fold lower than griseofulvin, reduced the microconidia viability of T. mentagrophytes and T. rubrum by 100%, whereas griseofulvin decreased their viability by only 50% and 0%, respectively. The action mechanism of peptides involved cell wall damage, membrane pore formation and loss of cytoplasmic content. Peptides also induced overproduction of reactive oxygen species (ROS) and enhanced the activity of griseofulvin 10‐fold against both fungi, suggesting synergistic effects, and eliminated the toxicity of this drug to human erythrocytes. Docking analysis revealed ionic and hydrophobic interactions between peptides and griseofulvin, which may explain the decline of griseofulvin toxicity when mixed with peptides. Conclusion Therefore, our results strongly suggest six peptides with high potential to be employed alone as new drugs or as adjuvants to enhance the activity and decrease the toxicity of griseofulvin.

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“…These HDP mimetics were prime candidates for anti-fungal drug development, for C. albicans grown long-term at sub-minimum inhibitory concentration (MIC) did not develop resistance to these mimetics [ 11 ] and they appeared to not affect commensal oral bacteria or biofilms [ 10 ]. These drugs also are active in vivo, both in an invasive candidiasis model and in an oral candidiasis model [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis

Chowdhury

Ryan

Cherabuddi

et al. 2018

JoF

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Invasive candidiasis caused by Candida albicans and non-albicans Candida (NAC) present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP) exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC) in the µg/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3–4 logs after 24 h in a dose-dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis.

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Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism

Cited by 34 publications

References 47 publications

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

Antidermatophytic activity of synthetic peptides: Action mechanisms and clinical application as adjuvants to enhance the activity and decrease the toxicity of Griseofulvin

Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis

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