scholarly journals Cathelicidin-inspired antimicrobial peptides as novel antifungal compounds

2020 ◽  
Vol 58 (8) ◽  
pp. 1073-1084
Author(s):  
Martin van Eijk ◽  
Stephanie Boerefijn ◽  
Lida Cen ◽  
Marisela Rosa ◽  
Marnix J H Morren ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Metabolic Activity ◽  
Fungal Infections ◽  
Fungal Species ◽  
Antifungal Compounds ◽  
Candida Auris ◽  
Low Concentrations ◽  
Wide Range ◽  
Eskape Pathogens ◽  
Near Future

Abstract Fungal infections in humans are increasing worldwide and are currently mostly treated with a relative limited set of antifungals. Resistance to antifungals is increasing, for example, in Aspergillus fumigatus and Candida auris, and expected to increase for many medically relevant fungal species in the near future. We have developed and patented a set of cathelicidin-inspired antimicrobial peptides termed ‘PepBiotics’. These peptides were initially selected for their bactericidal activity against clinically relevant Pseudomonas aeruginosa and Staphylococcus aureus isolates derived from patients with cystic fibrosis and are active against a wide range of bacteria (ESKAPE pathogens). We now report results from studies that were designed to investigate the antifungal activity of PepBiotics against a set of medically relevant species encompassing species of Aspergillus, Candida, Cryptococcus, Fusarium, Malassezia, and Talaromyces. We characterized a subset of PepBiotics and show that these peptides strongly affected metabolic activity and/or growth of a set of medically relevant fungal species, including azole-resistant A. fumigatus isolates. PepBiotics showed a strong inhibitory activity against a large variety of filamentous fungi and yeasts species at low concentrations (≤1 μM) and were fungicidal for at least a subset of these fungal species. Interestingly, the concentration of PepBiotics required to interfere with growth or metabolic activity varied between different fungal species or even between isolates of the same fungal species. This study shows that PepBiotics display strong potential for use as novel antifungal compounds to fight a large variety of clinically relevant fungal species.

Antimicrobial Peptides - Small but Mighty Weapons for Plants to Fight Phytopathogens

2019 ◽  
Vol 26 (10) ◽  
pp. 720-742 ◽  
Author(s):  
Kaushik Das ◽  
Karabi Datta ◽  
Subhasis Karmakar ◽  
Swapan K. Datta
Keyword(s):  
Antimicrobial Peptides ◽  
Durable Resistance ◽  
Defense Responses ◽  
Defense System ◽  
Biotechnological Potential ◽  
Functional Aspects ◽  
Low Concentrations ◽  
Wide Range ◽  
Vital Component ◽  
Pathogen Entry

Antimicrobial Peptides (AMPs) have diverse structures, varied modes of actions, and can inhibit the growth of a wide range of pathogens at low concentrations. Plants are constantly under attack by a wide range of phytopathogens causing massive yield losses worldwide. To combat these pathogens, nature has armed plants with a battery of defense responses including Antimicrobial Peptides (AMPs). These peptides form a vital component of the two-tier plant defense system. They are constitutively expressed as part of the pre-existing first line of defense against pathogen entry. When a pathogen overcomes this barrier, it faces the inducible defense system, which responds to specific molecular or effector patterns by launching an arsenal of defense responses including the production of AMPs. This review emphasizes the structural and functional aspects of different plant-derived AMPs, their homology with AMPs from other organisms, and how their biotechnological potential could generate durable resistance in a wide range of crops against different classes of phytopathogens in an environmentally friendly way without phenotypic cost.

scholarly journals In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 355
Author(s):  
Unai Caballero ◽  
Sarah Kim ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Valvanera Vozmediano ◽  
...  
Keyword(s):  
Interaction Model ◽  
Antifungal Drugs ◽  
Health Concern ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Wide Range ◽  
Time Kill

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.

scholarly journals 1258. Activity of a Series of Investigational Compounds Tested Against Invasive Fungal Isolates

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S645-S646
Author(s):  
Paul R Rhomberg ◽  
Shawn A Messer ◽  
Richard W Scott ◽  
Simon D P Baugh ◽  
Michael A Pfaller ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Chemical Diversity ◽  
Candida Auris ◽  
Services Research ◽  
Defense Proteins ◽  
Fungal Isolates ◽  
Wide Range ◽  
Cryptococcus Spp ◽  
Center Research ◽  
Research Grant

Abstract Background Fox Chase Chemical Diversity Center (FCC) is developing non-peptide analogs of host defense proteins for the treatment of invasive fungal infections mainly caused by Candida (CAN) and Aspergillus (ASP). We evaluated the activity of 6 novel compounds and 2 comparators against 150 isolates from 15 fungal groups. Methods Susceptibility testing was performed per CLSI broth microdilution methods for investigational compounds and comparators against 70 CAN and 40 ASP isolates in addition to 10 Cryptococcus spp. (CRYP), 10 Fusarium spp. (FUS), 10 Mucorales, and 10 Scedosporium spp. (SCED) isolates from recent (2017-2019) clinical infections. MIC results were determined as ≥ 50% reduction at 24 and 72 hours for CAN and CRYP respectively, and 100% reduction at 24, 72, and 48 hours for Mucorales, SCED, and other moulds, respectively. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied for comparators. Results Compounds FC10790, FC11083, FC11212, and FC11275 had MIC50 results at ≤ 0.015 mg/L and MIC90 results at ≤ 0.015 to 0.12 mg/L against CRYP, ASP, and FUS isolates. Compounds FC5096 and FC11022 were 2- to 4-fold less active while demonstrating MIC50 and MIC90 results of 0.03 to 0.5 mg/L against CAN, CRYP, ASP, and FUS isolates. The Mucorales isolate set showed the widest range of MIC results for FC compounds. FC10790 exhibited the greatest potency with a MIC50/90 at 0.5/2 mg/L. FC compounds showed potent activity against SCED with MIC90 results of 0.03 to 0.25 mg/L. Fluconazole showed a wide range of MIC results, from 0.06 to >64 mg/L, but the highest results observed were for Candida auris (MIC50/90, 64/ > 64 mg/L) and Candida krusei (MIC50/90; 16/32 mg/L). Itraconazole was active against all ASP (MIC50/90, 1/1 mg/L), but showed poor activity against FUS (MIC50/90, > 8/ > 8 mg/L). Amphotericin B showed a narrow range of MIC results (0.5 to 2 mg/L) for all isolates except 1 ASP and most SCED. Conclusion Novel FCC compounds showed equal or greater activity than comparators against most CAN, ASP, SCED, and FUS. FC10790, FC11212, and FC11275 showed the greatest activity against all tested fungal isolates. development of this series of compounds for clinical studies. Table 1 Disclosures Paul R. Rhomberg, n/a, Cidara Therapeutics (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Merck (Research Grant or Support) Shawn A. Messer, PhD, Amplyx Pharmaceuticals (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support) Richard W. Scott, PhD, Fox Chase Chemical Diversity Center (Employee) Simon DP Baugh, PhD, Fox Chase Chemical Diversity Center (Employee) Michael A. Pfaller, MD, Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Cecilia G. Carvalhaes, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)

Vancomycin enhances growth and virulence of Trichosporon spp. planktonic cells and biofilms

2021 ◽  
Author(s):  
Rossana de Aguiar Cordeiro ◽  
Bruno Nascimento da Silva ◽  
Ana Luiza Ribeiro de Aguiar ◽  
Livia Maria Galdino Pereira ◽  
Fernando Victor Monteiro Portela ◽  
...  
Keyword(s):  
Metabolic Activity ◽  
Fungal Infections ◽  
Tolerance Induction ◽  
Microscopic Analysis ◽  
Fungal Species ◽  
Planktonic Cells ◽  
Persister Cells ◽  
Candida Spp ◽  
Patients At Risk

Abstract Invasive fungal infections (IFIs) are important worldwide health problem, affecting the growing population of immunocompromised patients. Although the majority of IFIs are caused by Candida spp., other fungal species have been increasingly recognized as relevant opportunistic pathogens. Trichosporon spp. are members of skin and gut human microbiota. Since 1980’s, invasive trichosporonosis has been considered a significant cause of fungemia in patients with hematological malignancies. As prolonged antibiotic therapy is an important risk factor for IFIs, the present study investigated if vancomycin enhances growth and virulence of Trichosporon. Vancomycin was tested against T. inkin (n = 6) and T. asahii (n = 6) clinical strains. Planktonic cells were evaluated for their metabolic activity and virulence against Caenorhabditis elegans. Biofilms were evaluated for metabolic activity, biomass production, amphotericin B tolerance, induction of persister cells, and ultrastructure. Vancomycin stimulated planktonic growth of Trichosporon spp., increased tolerance to AMB, and potentiates virulence against C. elegans. Vancomycin stimulated growth (metabolic activity and biomass) of Trichosporon spp. biofilms during all stages of development. The antibiotic increased the number of persister cells inside Trichosporon biofilms. These cells showed higher tolerance to AMB than persister cells from VAN-free biofilms. Microscopic analysis showed that VAN increased production of extracellular matrix and cells in T. inkin and T. asahii biofilms. These results suggest that antibiotic exposure may have a direct impact on the pathophysiology of opportunistic trichosporonosis in patients at risk. Lay abstract This study showed that the vancomycin stimulated Trichosporon growth, induced morphological and physiological changes on their biofilms, and also enhanced their in vivo virulence. Although speculative, the stimulatory effect of vancomycin on fungal cells should be considered in a clinical scenario.

scholarly journals 2-Acryloyl-4,5-methylenedioxyphenol: A Small Molecule Endowed with Antidermatophytic Activity

2019 ◽  
Vol 16 (4) ◽  
pp. 461-466
Author(s):  
Marco Zuccolo ◽  
Sabrina Dallavalle ◽  
Raffaella Cincinelli ◽  
Luce Mattio ◽  
Stefania Mazzini ◽  
...  
Keyword(s):  
Small Molecule ◽  
Natural Compound ◽  
Fungal Infections ◽  
Positive Control ◽  
Fungal Species ◽  
Fungal Diseases ◽  
Antifungal Compounds ◽  
Starting Point ◽  
Antidermatophytic Activity

Background: Superficial fungal infections are the most common fungal diseases in humans, affecting more than 25% of the population worldwide. Methods: In the present study, we have investigated the activity of kakuol, a natural compound isolated from the rhizomes of Asarum sieboldii, and some analogues, against various dermatophytes and pharmacologically relevant yeasts. Results: One of the tested compounds, 2-acryloyl-4,5-methylenedioxyphenol, showed a broadspectrum activity against most of the fungal species assayed, resulting particularly effective against dermatophyte strains (MIC values in the range of 0.25-0.5 µg/mL, two/four-fold lower than the positive control miconazole). Conclusion: The results suggest that this molecule can be considered a promising starting point for the development of new antifungal compounds.

scholarly journals In vitro activity of a novel antifungal compound, MYC-053, against clinically significant antifungal-resistant strains of Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp

2018 ◽  
Author(s):  
G Tetz ◽  
M Collins ◽  
D Vikina ◽  
V Tetz
Keyword(s):  
Cryptococcus Neoformans ◽  
Candida Glabrata ◽  
Fungal Infections ◽  
Therapeutic Window ◽  
Antifungal Compound ◽  
Antifungal Compounds ◽  
Candida Auris ◽  
Treatment And Prevention ◽  
Resistant Strains

ABSTRACTAn urgent need exists for new antifungal compounds to treat fungal infections in immunocompromised patients. The aim of the current study was to investigate the potency of a novel antifungal compound, MYC-053, against the emerging yeast and yeast-like pathogens Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp. MYC-053 was equally effective against the susceptible control strains, clinical isolates, and resistant strains, with the minimum inhibitory concentrations (MIC) of 0.125–4.0 μg/mL. Notably, unlike other antifungal compounds, MYC-053 was effective against Pneumocystis isolates. MYC-053 was highly effective against preformed 48-h-old yeast biofilms, with the minimal biofilm eradication concentrations equal to 1–4 times MIC. The compound was not cytotoxic against L2 and A549 cell lines at concentrations over 100 μg/ml. Further, it possessed no apparent hemolytic activity up to 1000 μg/ml (the highest concentration tested). Overall, these data indicated that MYC-053 has a broad therapeutic window and may be developed into a promising antifungal agent for the treatment and prevention of invasive fungal infections caused by yeasts and yeast-like fungi in neutropenic patients.

scholarly journals Photoinactivation of catalase sensitizes Candida albicans and Candida auris to ROS-producing agents and immune cells

2021 ◽  
Author(s):  
Pu-Ting Dong ◽  
Yuewei Zhan ◽  
Sebastian Jusuf ◽  
Jie Hui ◽  
Zeina Dagher ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Blue Light ◽  
Optical Switch ◽  
Multidrug Resistant ◽  
Fungal Species ◽  
Candida Auris ◽  
Fungal Cell ◽  
Wide Range ◽  
Inactivation Mechanism ◽  
Macrophage Killing

Nearly all organisms found in nature have evolved and developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme-containing tetramer protein expressed in a broad range of aerobic fungi, has been utilized as an essential enzymatic ROS detoxifying mechanism, and shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal cell survival and host invasion. Here, we demonstrate that catalase inactivation with blue light renders fungal cells highly susceptible to ROS attack, thus resembling a 'strength-to-weakness optical switch'. To unveil catalase as the underlying molecular target of blue light and its inactivation mechanism, we systematically compared wild-type Candida albicans to a catalase-deficient mutant strain for susceptibility to ROS in the absence/presence of 410 nm treatment. Upon testing on a wide range of fungal species and strains, we found that intracellular catalase could be effectively and universally inactivated by 410 nm blue light. We find that the photoinactivation of catalase in combination with ROS-generating agents is highly effective and potent in achieving full eradication of multiple fungal species and strains, including multiple clinical strains of Candida auris, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a Candida albicans-induced mouse model of skin abrasion. Taken together, our findings offer a novel catalase-photoinactivation approach to address multidrug-resistant Candida infections.

scholarly journals A second generation fungerp analog SCY-247, shows potent in vitro activity against Candida auris and other clinically relevant fungal isolates

2020 ◽  
pp. AAC.01988-20
Author(s):  
Sherman Chu ◽  
Lisa Long ◽  
Rania Sherif ◽  
Thomas S. McCormick ◽  
Katyna Borroto-Esoda ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Second Generation ◽  
Fungal Infections ◽  
Parent Compound ◽  
Fungal Species ◽  
Antifungal Compound ◽  
Candida Auris ◽  
Fungal Cell ◽  
Antifungal Properties

Due to the increase of antifungal drug resistance and difficulties associated with drug administration, new antifungal agents for invasive fungal infections are needed. SCY-247 is a second-generation fungerp antifungal compound that interferes with the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan. We conducted an extensive antifungal screen of SCY-247 against yeast and mold strains compared with the parent compound ibrexafungerp (IBX, formerly SCY-078) to evaluate the in vitro antifungal properties of SCY-247. SCY-247 demonstrated similar activity to IBX against all of the organisms tested. Moreover, SCY-247 showed a higher percentage of fungicidal activity against the panel of yeast and mold isolates compared to IBX. Notably, SCY-247 showed considerable antifungal properties against numerous strains of Candida auris. Additionally, SCY-247 retained its antifungal activity when evaluated in the presence of synthetic urine, indicating that SCY-247 maintains activity and structural stability under environments with decreased pH levels. Finally, a time-kill study showed SCY-247 has potent anti-Candida, Aspergillus, and Scedosporium activity. In summary, SCY-247 has potent antifungal activity against various fungal species, indicating that further studies on this fungerp analog are warranted.

scholarly journals Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus

2020 ◽  
Vol 6 (2) ◽  
pp. 65
Author(s):  
Eloise Ballard ◽  
Raif Yucel ◽  
Willem J. G. Melchers ◽  
Alistair J. P. Brown ◽  
Paul E. Verweij ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Antimicrobial Peptides ◽  
Aspergillus Fumigatus ◽  
Metabolic Activity ◽  
Hyphal Growth ◽  
Human Fungal Pathogen ◽  
Imaging Flow Cytometry ◽  
Wide Range ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Antimicrobial peptides and proteins (AMPs) provide an important line of defence against invading microorganisms. However, the activity of AMPs against the human fungal pathogen Aspergillus fumigatus remains poorly understood. Therefore, the aim of this study was to characterise the anti-Aspergillus activity of specific human AMPs, and to determine whether A. fumigatus can possess resistance to specific AMPs, as a result of in-host adaptation. AMPs were tested against a wide range of clinical isolates of various origins (including cystic fibrosis patients, as well as patients with chronic and acute aspergillosis). We also tested a series of isogenic A. fumigatus isolates obtained from a single patient over a period of 2 years. A range of environmental isolates, obtained from soil in Scotland, was also included. Firstly, the activity of specific peptides was assessed against hyphae using a measure of fungal metabolic activity. Secondly, the activity of specific peptides was assessed against germinating conidia, using imaging flow cytometry as a measure of hyphal growth. We showed that lysozyme and histones inhibited hyphal metabolic activity in all the A. fumigatus isolates tested in a dose-dependent fashion. In addition, imaging flow cytometry revealed that histones, β-defensin-1 and lactoferrin inhibited the germination of A. fumigatus conidia.

scholarly journals The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

2020 ◽  
Vol 6 (3) ◽  
pp. 138 ◽  
Author(s):  
Amir Arastehfar ◽  
Cornelia Lass-Flörl ◽  
Rocio Garcia-Rubio ◽  
Farnaz Daneshnia ◽  
Macit Ilkit ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Candida Auris ◽  
Recent Emergence ◽  
Invasive Infections

Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

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