Synthetic Histidine-Rich Peptides Inhibit Candida Species and Other Fungi In Vitro: Role of Endocytosis and Treatment Implications

ABSTRACT A family of histidine-rich peptides, histatins, is secreted by the parotid gland in mammals and exhibits marked inhibitory activity against a number of Candida species. We were particularly interested in the mechanism by which histidine-rich peptides inhibit fungal growth, because our laboratory has synthesized a variety of such peptides for drug and nucleic acid delivery. In contrast to naturally occurring peptides that are linear, peptides made on synthesizers can be varied with respect to their degrees of branching. Using this technology, we explored whether histidine-lysine (HK) polymers of different complexities and degrees of branching affect the growth of several species of Candida. Polymers with higher degrees of branching were progressively more effective against Candida albicans, with the four-branched polymer, H2K4b, most effective. Furthermore, H2K4b accumulated efficiently in C. albicans, which may indicate its ability to transport other antifungal agents intracellularly. Although H2K4b had greater antifungal activity than histatin 5, their mechanisms were similar. Toxicity in C. albicans induced by histatin 5 or branched HK peptides was markedly reduced by 4,4′-diisothiocyanato-stilbene-2,2′-disulfonate, an inhibitor of anion channels. We also determined that bafilomycin A1, an inhibitor of endosomal acidification, significantly decreased the antifungal activity of H2K4b. This suggests that the pH-buffering and subsequent endosomal-disrupting properties of histidine-rich peptides have a role in their antifungal activity. Moreover, the ability of the histidine component of these peptides to disrupt endosomes, which allows their escape from the lysosomal pathway, may explain why these peptides are both effective antifungal agents and nucleic acid delivery carriers.

Download Full-text

Synthesis and Antifungal Activity of Coumarins Derivatives Against Sporothrix spp.

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180221115508 ◽

2018 ◽

Vol 18 (2) ◽

pp. 164-171 ◽

Cited By ~ 4

Author(s):

Luana da S.M. Forezi ◽

Luana Pereira Borba-Santos ◽

Mariana F.C. Cardoso ◽

Vitor F. Ferreira ◽

Sonia Rozental ◽

...

Keyword(s):

Antifungal Activity ◽

Antifungal Agents ◽

Sporothrix Schenckii ◽

Public Health Problem ◽

Domestic Animals ◽

Coumarin Derivatives ◽

Sporothrix Brasiliensis ◽

Synthetic Routes ◽

Effective Drugs

Sporotrichosis is a serious public health problem in Brazil that affects human patients and domestic animals, mainly cats. Thus, the search for new antifungal agents is required also due to the emergence and to the lack of effective drugs available in the therapeutic arsenal. The aim of this study was to evaluate the in vitro antifungal profile of two synthetic series of coumarin derivatives against Sporothrix schenckii and Sporothrix brasiliensis. The three-components synthetic routes used for the preparation of coumarin derivatives have proved to be quite efficient and compounds 16 and 17 have been prepared in good yields. The inhibitory activity of nineteen synthetic coumarins derivatives 16a-i and 17a-j were evaluated against Sporothrix spp. yeasts and the most potent compounds were 16b and 17i. However, according to concentrations able to inhibit (minimum inhibitory concentrations) and kill (minimum fungicidal concentrations) the cells, 17i was more effective than 16b against Sporothrix spp. Thus, 17i exhibited good antifungal activity against S. brasiliensis and S. schenckii, suggesting that it is an important scaffold for the development of novel antifungal agents.

Download Full-text

Bacillus megaterium-Mediated Synthesis of Selenium Nanoparticles and Their Antifungal Activity against Rhizoctonia solani in Faba Bean Plants

Journal of Fungi ◽

10.3390/jof7030195 ◽

2021 ◽

Vol 7 (3) ◽

pp. 195

Author(s):

Amr H. Hashem ◽

Amer M. Abdelaziz ◽

Ahmed A. Askar ◽

Hossam M. Fouda ◽

Ahmed M. A. Khalil ◽

...

Keyword(s):

Antifungal Activity ◽

Vicia Faba ◽

Root Rot ◽

Antifungal Agents ◽

Damping Off ◽

Growth Promoters ◽

Root Rot Disease ◽

Rot Disease

Rhizoctonia root-rot disease causes severe economic losses in a wide range of crops, including Vicia faba worldwide. Currently, biosynthesized nanoparticles have become super-growth promoters as well as antifungal agents. In this study, biosynthesized selenium nanoparticles (Se-NPs) have been examined as growth promoters as well as antifungal agents against Rhizoctonia solani RCMB 031001 in vitro and in vivo. Se-NPs were synthesized biologically by Bacillus megaterium ATCC 55000 and characterized by using UV-Vis spectroscopy, XRD, dynamic light scattering (DLS), and transmission electron microscopy (TEM) imaging. TEM and DLS images showed that Se-NPs are mono-dispersed spheres with a mean diameter of 41.2 nm. Se-NPs improved healthy Vicia faba cv. Giza 716 seed germination, morphological, metabolic indicators, and yield. Furthermore, Se-NPs exhibited influential antifungal activity against R. solani in vitro as well as in vivo. Results revealed that minimum inhibition and minimum fungicidal concentrations of Se-NPs were 0.0625 and 1 mM, respectively. Moreover, Se-NPs were able to decrease the pre-and post-emergence of R. solani damping-off and minimize the severity of root rot disease. The most effective treatment method is found when soaking and spraying were used with each other followed by spraying and then soaking individually. Likewise, Se-NPs improve morphological and metabolic indicators and yield significantly compared with infected control. In conclusion, biosynthesized Se-NPs by B. megaterium ATCC 55000 are a promising and effective agent against R. solani damping-off and root rot diseases in Vicia faba as well as plant growth inducer.

Download Full-text

IMMU-53. STING-ING GLIOBLASTOMA WITH SPHERICAL NUCLEIC ACIDS

Neuro-Oncology ◽

10.1093/neuonc/noab196.412 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi104-vi105

Author(s):

Akanksha Mahajan ◽

Lisa Hurley ◽

Serena Tommasini-Ghelfi ◽

Corey Dussold ◽

Alexander Stegh ◽

...

Keyword(s):

Nucleic Acid ◽

High Surface ◽

Biological Properties ◽

Innate Immune ◽

Limiting Factors ◽

Nucleic Acid Delivery ◽

Sting Pathway ◽

Spherical Nucleic Acids

Abstract The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that are amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e.,the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently completed early clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway in vitro and in vivo. In a poorly immunogenic and highly aggressive syngeneic mouse glioma model, in which tumours were well-established, only one dose of intranasal treatment with STING-SNAs decelerated tumour growth, improved survival and importantly, was well-tolerated. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites via intranasal route, exploits the binding of dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.

Download Full-text

Low In Vitro Antifungal Activity of Tavaborole against Yeasts and Molds from Onychomycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01632-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 4

Author(s):

Mahdi Abastabar ◽

Iman Haghani ◽

Tahereh Shokohi ◽

Mohammad Taghi Hedayati ◽

Seyed Reza Aghili ◽

...

Keyword(s):

Antifungal Activity ◽

Antifungal Agents ◽

Antifungal Drug ◽

Content Type ◽

Fungal Isolates ◽

Yeasts And Molds ◽

Low Activity ◽

In Vitro Antifungal Activity

ABSTRACT The in vitro activity of tavaborole, an FDA-approved antifungal drug, was compared to that of four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine, and fluconazole, the principal choices for treatment of onychomycosis. Thus, it appears that tavaborole is not a candidate for the treatment of onychomycosis due to Candida species, Aspergillus species, and dermatophytes.

Download Full-text

Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy

Molecules ◽

10.3390/molecules25122866 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2866 ◽

Cited By ~ 8

Author(s):

Aniket Wahane ◽

Akaash Waghmode ◽

Alexander Kapphahn ◽

Karishma Dhuri ◽

Anisha Gupta ◽

...

Keyword(s):

Gene Therapy ◽

Nucleic Acid ◽

Messenger Rna ◽

Viral Vectors ◽

Cationic Lipids ◽

Nucleic Acid Delivery ◽

Nucleic Acid Analogs ◽

Organ Specific ◽

Interfering Rna

The field of gene therapy has experienced an insurgence of attention for its widespread ability to regulate gene expression by targeting genomic DNA, messenger RNA, microRNA, and short-interfering RNA for treating malignant and non-malignant disorders. Numerous nucleic acid analogs have been developed to target coding or non-coding sequences of the human genome for gene regulation. However, broader clinical applications of nucleic acid analogs have been limited due to their poor cell or organ-specific delivery. To resolve these issues, non-viral vectors based on nanoparticles, liposomes, and polyplexes have been developed to date. This review is centered on non-viral vectors mainly comprising of cationic lipids and polymers for nucleic acid-based delivery for numerous gene therapy-based applications.

Download Full-text

Crucial Role of Nucleic Acid Sensing via Endosomal Toll-Like Receptors for the Defense of Streptococcus pyogenes in vitro and in vivo

Frontiers in Immunology ◽

10.3389/fimmu.2019.00198 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Anna Hafner ◽

Ulrike Kolbe ◽

Isabel Freund ◽

Virginia Castiglia ◽

Pavel Kovarik ◽

...

Keyword(s):

Nucleic Acid ◽

Streptococcus Pyogenes ◽

Crucial Role ◽

Toll Like Receptors

Download Full-text

Cationic DOPC-Detergent Conjugates for Safe and Efficient in Vitro and in Vivo Nucleic Acid Delivery

ChemBioChem ◽

10.1002/cbic.201600302 ◽

2016 ◽

Vol 17 (18) ◽

pp. 1771-1783 ◽

Cited By ~ 5

Author(s):

Philippe Pierrat ◽

Anne Casset ◽

Pascal Didier ◽

Dimitri Kereselidze ◽

Marie Lux ◽

...

Keyword(s):

Nucleic Acid ◽

Nucleic Acid Delivery

Download Full-text

7-Chloroquinolin-4-yl Arylhydrazone Derivatives: Synthesis and Antifungal Activity

The Scientific World JOURNAL ◽

10.1100/tsw.2011.141 ◽

2011 ◽

Vol 11 ◽

pp. 1489-1495 ◽

Cited By ~ 11

Author(s):

Auri R. Duval ◽

Pedro H. Carvalho ◽

Maieli C. Soares ◽

Daniela P. Gouvêa ◽

Geonir M. Siqueira ◽

...

Keyword(s):

Antifungal Activity ◽

Rational Design ◽

Antifungal Agents ◽

Inhibitory Concentration ◽

First Line ◽

Minimum Fungicidal Concentration ◽

Starting Point ◽

Line Drug ◽

In Vitro Antifungal Activity

Fifteen 7-chloro-4-arylhydrazonequinolines have been evaluated for their in vitro antifungal activity against eight oral fungi:Candida albicans, C. parapsilosis, C. lipolytica, C. tropicalis, C. famata, C. glabrata, Rhodutorula mucilaginosa, andR. glutinis. Several compounds exhibited minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) activities comparable with the first-line drug fluconazole. These results could be considered as an important starting point for the rational design of new antifungal agents.

Download Full-text

Inhibition of Intramacrophage Growth ofPenicillium marneffei by 4-Aminoquinolines

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.5.1450-1455.2001 ◽

2001 ◽

Vol 45 (5) ◽

pp. 1450-1455 ◽

Cited By ~ 9

Author(s):

Donatella Taramelli ◽

Clara Tognazioli ◽

F. Ravagnani ◽

O. Leopardi ◽

G. Giannulis ◽

...

Keyword(s):

Antifungal Activity ◽

Iron Acquisition ◽

Fungal Growth ◽

Antimicrobial Activities ◽

Ammonium Citrate ◽

Immunodeficiency Virus ◽

Dependent Inhibition ◽

J774 Cells ◽

Dose Dependent Inhibition

ABSTRACT The antimicrobial activities of chloroquine (CQ) and several 4-aminoquinoline drugs were tested against Penicillium marneffei, an opportunistic fungus that invades and grows inside macrophages and causes disseminated infection in AIDS patients. Human THP1 and mouse J774 macrophages were infected in vitro with P. marneffei conidia and treated with different doses of drugs for 24 to 48 h followed by cell lysis and the counting of P. marneffei CFU. CQ and amodiaquine exerted a dose-dependent inhibition of fungal growth, whereas quinine and artemisinin were fungistatic and not fungicidal. The antifungal activity of CQ was not due to an impairment of fungal iron acquisition in that it was not reversed by the addition of iron nitrilotriacetate, FeCl3, or iron ammonium citrate. Perl's staining indicated that CQ did not alter the ability of J774 cells to acquire iron from the medium. Most likely, CQ's antifungal activity is due to an increase in the intravacuolar pH and a disruption of pH-dependent metabolic processes. Indeed, we demonstrate that (i) bafilomycin A1 and ammonium chloride, two agents known to alkalinize intracellular vesicles by different mechanisms, were inhibitory as well and (ii) a newly synthesized 4-amino-7-chloroquinoline molecule (compound 9), lacking the terminal amino side chain of CQ that assists in drug accumulation, did not inhibit P. marneffei growth. These results suggest that CQ has a potential for use in prophylaxis of P. marneffeiinfections in human immunodeficiency virus-infected patients in countries where P. marneffei is endemic.

Download Full-text