Ultrashort Peptide Bioconjugates Are Exclusively Antifungal Agents and Synergize with Cyclodextrin and Amphotericin B (original) (raw)
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In the present study, we investigated the antifungal activity and cytotoxicity of a novel membrane-active peptide, KKVVFKVKFKK (MP). MP inhibited the growth of various pathogenic fungi isolated from patients and of fluconazole-resistant fungi at concentrations of 2 to 32 μg/ml. MP had potent fungicidal activity; the minimal fungicidal concentrations of the peptide were no more than fourfold greater than the MICs. Time course experiments of MP-induced killing of Candida albicans ATCC 36232 showed that the rate of killing was rapid and depended on the concentration of MP. MP had a strong synergism with other antifungal drugs; the fractional inhibitory concentration index values of MP with amphotericin B and fluconazole for C. albicans were 0.16 and 0.02, respectively. The 50% inhibitory concentrations of MP for NIH 3T3 and Jurkat cells were approximately 100 times higher than the MIC for C. albicansATCC 36232, indicating that MP had high selectivity between the fungal and mammalian ce...
Journal of Biological Chemistry, 2004
We report on the synthesis, biological function, and a plausible mode of action of a new group of lipopeptides with potent antifungal and antibacterial activities. These lipopeptides are derived from positively charged peptides containing D-and L-amino acids (diastereomers) that are palmitoylated (PA) at their N terminus. The peptides investigated have the sequence K 4 X 7 W, where X designates Gly, Ala, Val, or Leu (designated D-X peptides). The data revealed that PAD -G and PAD A gained potent antibacterial and antifungal activity despite the fact that both parental peptides were completely devoid of any activity toward microorganisms and model phospholipid membranes. In contrast, PAD -L lost the potent antibacterial activity of the parental peptide but gained and preserved partial antifungal activity. Interestingly, both D-V and its palmitoylated analog were inactive toward bacteria, and only the palmitoylated peptide was highly potent toward yeast. Both PAD -L and PAD -V lipopeptides were also endowed with hemolytic activity. Mode of action studies were performed by using tryptophan fluorescence and attenuated total reflectance Fourier transform infrared and circular dichroism spectroscopy as well as transmembrane depolarization assays with bacteria and fungi. The data suggest that the lipopeptides act by increasing the permeability of the cell membrane and that differences in their potency and target specificity are the result of differences in their oligomeric state and ability to dissociate and insert into the cytoplasmic membrane. These results provide insight regarding a new approach of modulating hydrophobicity and the self-assembly of non-membrane interacting peptides in order to endow them with both antibacterial and antifungal activities urgently needed to combat bacterial and fungal infections.
Biochemical and Biophysical Research Communications, 2010
Short antimicrobial peptides with nine and eleven residues were developed against several clinically important bacterial and fungal pathogens (specifically Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Fusarium solani). Twelve analogues of previously reported peptides BP76 (KKLFKKILKFL) and Pac-525 (KWRRWVRWI) were designed, synthesized, and tested for their antimicrobial activities. Two of our eleven amino acid peptides, P11-5 (GKLFKKILKIL) and P11-6 (KKLIKKIL-KIL), have very low MICs of 3.1-12.5 lg ml À1 against all five pathogens. The MICs of these two peptides against S. aureus, C. albicans and F. solani are four to ten times lower than the corresponding MICs of the reference peptide BP76. P9-4 (KWRRWIRWL), our newly designed nine-amino acid analogue, also has particularly low MICs of 3.1-6.2 lg ml À1 against four of the tested pathogens; these MICs are two to eight times lower than those reported for Pac-525 (6.2-50 lg ml À1 ).These new peptides (P11-5, P11-6 and P9-4) also exhibit improved stability in the presence of salts, and have low cytotoxicity as shown by the hemolysis and MTT assays. From the results of field-emission scanning electron microscopy, membrane depolarization and dye-leakage assays, we propose that these peptides exert their action by disrupting membrane lipids. Molecular dynamics simulation studies confirm that P11-6 peptide maintains relatively stable helical structure and exerts more perturbation action on the order of acyl tail of lipid bilayer.
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Bioorganic & medicinal …, 2011
Echinocandins are a novel class of macrocyclic antifungal peptides that act by inhibiting the b-(1,3)-Dglucan synthase complex, which is not present in mammalian cells. Due to the large number of hydroxyl groups present in these complex macrocyclic lipopeptides, most structure-activity relationship studies have relied upon semisynthetic derivatives. In order to probe the influence of the cyclic peptide backbone on the antifungal activity we developed a successful strategy for the synthesis of novel echinocandins analogues by on-resin ring closing metathesis or disulfide formation. The specific minimum inhibitory activity of each mimic was determined against Candida albicans. Our results indicate that ring size is an important factor for antifungal activity.
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2006
Background and objectives: Candida species are problematic opportunistic pathogens in the hospital setting, where they are frequently associated with opportunistic infections of indwelling medical devices. There are only a few effective classes of antifungal agents currently available, and some species, such as Candida lusitaniae, Candida glabrata and Candida krusei, are intrinsically resistant to some of these drugs, further reducing existing therapeutic options. We have recently developed synthetic, non-amphipathic cationic antimicrobial peptides (CAPs) based on the structure of native hydrophobic membrane-spanning domains of integral membrane proteins. In this article, we report on the activity of these CAPs and new variants thereof against eight Candida species.
Peptides, 2011
In the present work, we investigated the antifungal activity of two de novo designed, antimicrobial peptides VS2 and VS3, incorporating unnatural amino acid ␣,-dehydrophenylalanine ( Phe). We observed that the low-hemolytic peptides could irreversibly inhibit the growth of various Candida species and multidrug resistance strains at MIC 80 values ranging from 15.62 M to 250 M. Synergy experiments showed that MIC 80 of the peptides was drastically reduced in combination with an antifungal drug fluconazole. The dye PI uptake assay was used to demonstrate peptide induced cell membrane permeabilization. Intracellular localization of the FITC-labeled peptides in Candida albicans was studied by confocal microscopy and FACS. Killing kinetics, PI uptake assay, and the intracellular presence of FITC-peptides suggested that growth inhibition is not solely a consequence of increased membrane permeabilization. We showed that entry of the peptide in Candida cells resulted in accumulation of reactive oxygen species (ROS) leading to cell necrosis. Morphological alteration in Candida cells caused by the peptides was visualized by electron microscopy. We propose that de novo designed VS2 and VS3 peptides have multiple detrimental effects on target fungi, which ultimately result in cell wall disruption and killing. Therefore, these peptides represent a good template for further design and development as antifungal agents.
Ultrashort antibacterial and antifungal lipopeptides
Proceedings of the National Academy of Sciences, 2006
Host-defense cationic antimicrobial peptides (Ϸ12-50 aa long) play an essential protective role in the innate immune system of all organisms. Lipopeptides, however, are produced only in bacteria and fungi during cultivation, and they are composed of specific lipophilic moieties attached to anionic peptides (six to seven amino acids). Here we report the following. (i) The attachment of an aliphatic chain to otherwise inert, cationic D,L tetrapeptides endows them with potent activity against various microorganisms including antibiotic resistance strains. (ii) Cell specificity is determined by the sequence of the short peptidic chain and the length of the aliphatic moiety. (iii) Despite the fact that the peptidic chains are very short, their mode of action involves permeation and disintegration of membranes, similar to that of many long antimicrobial peptides. Besides adding important information on the parameters necessary for host-defense lipopeptides to kill microorganisms, the simple composition of these lipopeptides and their diverse specificities should make them economically available, innate immunity-mimicking antimicrobial and antifungal compounds for various applications.
Peptide-based Antifungal Therapies against Emerging Infections
Drugs of the future, 2010
Acquired drug resistance to mycotic infections is rapidly emerging as a major medical problem. Opportunistic fungal infections create therapeutic challenges, particularly in high risk immunocompromised patients with AIDS, cancer, and those undergoing transplantation. Higher mortality and/or morbidity rates due to invasive mycosis have been increasing over the last 20 years, and in light of growing resistance to commonly used antibiotics, novel antifungal drugs and approaches are required. Currently there is considerable interest in antifungal peptides that are ubiquitous in plant and animal kingdoms. These small cationic peptides may have specific targets or may be multifunctional in their mechanism of action. On the basis of recent advances in protein engineering and solid phase syntheses, the utility and potential of selected peptides as efficient antifungal drugs with acceptable toxicity profiles are being realized. This review will discuss recent advances in peptide therapy for ...
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Molecules, 2021
Harmful fungi in nature not only cause diseases in plants, but also fungal infection and poisoning when people and animals eat food derived from crops contaminated with them. Unfortunately, such fungi are becoming increasingly more resistant to traditional synthetic antifungal drugs, which can make prevention and control work increasingly more difficult to achieve. This means they are potentially very harmful to human health and lifestyle. Antifungal peptides are natural substances produced by organisms to defend themselves against harmful fungi. As a result, they have become an important research object to help deal with harmful fungi and overcome their drug resistance. Moreover, they are expected to be developed into new therapeutic drugs against drug-resistant fungi in clinical application. This review focuses on antifungal peptides that have been isolated from bacteria, fungi, and other microorganisms to date. Their antifungal activity and factors affecting it are outlined in te...