Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

The emergence of infectious diseases promises to be one of the leading mortality factors in the healthcare sector. Although several drugs are available on the market, newly found microorganisms carrying multidrug resistance (MDR) against which existing drugs cannot function effectively, giving rise to escalated antibiotic dosage therapies and the need to develop novel drugs, which require time, money, and manpower. Thus, the exploitation of antimicrobials has led to the production of MDR bacteria, and their prevalence and growth are a major concern. Novel approaches to prevent antimicrobial drug resistance are in practice. Nanotechnology-based innovation provides physicians and patients the opportunity to overcome the crisis of drug resistance. Nanoparticles have promising potential in the healthcare sector. Recently, nanoparticles have been designed to address pathogenic microorganisms. A multitude of processes that can vary with various traits, including size, morphology, electrical charge, and surface coatings, allow researchers to develop novel composite antimicrobial substances for use in different applications performing antimicrobial activities. The antimicrobial activity of inorganic and carbon-based nanoparticles can be applied to various research, medical, and industrial uses in the future and offer a solution to the crisis of antimicrobial resistance to traditional approaches. Metal-based nanoparticles have also been extensively studied for many biomedical applications. In addition to reduced size and selectivity for bacteria, metal-based nanoparticles have proven effective against pathogens listed as a priority, according to the World Health Organization (WHO). Moreover, antimicrobial studies of nanoparticles were carried out not only in vitro but in vivo as well in order to investigate their efficacy. In addition, nanomaterials provide numerous opportunities for infection prevention, diagnosis, treatment, and biofilm control. This study emphasizes the antimicrobial effects of nanoparticles and contrasts nanoparticles’ with antibiotics’ role in the fight against pathogenic microorganisms. Future prospects revolve around developing new strategies and products to prevent, control, and treat microbial infections in humans and other animals, including viral infections seen in the current pandemic scenarios.

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“…[46] 1939 Gramicidin A is discovered as the first clinically effective topical antibiotic from the soil bacterium bacillus brevis. [47] 1939…”

Section: Time Periodmentioning

confidence: 99%

Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics

et al. 2021

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“…However, its prolonged application resulted in high host cytotoxicity. 65 In the present study, tyrocidine-derived peptide presented minimal cytotoxic effects against human cell lines (HeLa cells) and pretreated amoebae were able to restrict amoeba-mediated host cell cytopathogenicity for Acanthamoeba and Naegleria . The results from our peptide are motivating, as our data are indicative of minimal cytotoxicity.…”

Section: Discussionmentioning

confidence: 51%

Novel Antiamoebic Tyrocidine-Derived Peptide against Brain-Eating Amoebae

et al. 2022

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Acanthamoeba castellanii ( A. castellanii ) can cause Acanthamoeba keratitis, a sight-threatening infection, as well as a fatal brain infection termed granulomatous amoebic encephalitis, mostly in immunocompromised individuals. In contrast, Naegleria fowleri ( N. fowleri ) causes a deadly infection involving the central nervous system, recognized as primary amoebic encephalitis, mainly in individuals partaking in recreational water activities or those with nasal exposure to contaminated water. Worryingly, mortality rates due to these infections are more than 90%, suggesting the need to find alternative therapies. In this study, antiamoebic activity of a peptide based on the structure of the antibiotic tyrocidine was evaluated against A. castellanii and N. fowleri . The tyrocidine-derived peptide displayed significant amoebicidal efficacy against A. castellanii and N. fowleri . At 250 μg/mL, the peptide drastically reduced amoebae viability up to 13% and 21% after 2 h of incubation against N. fowleri and A. castellanii. , whereas, after 24 h of incubation, the peptide showed 86% and 94% amoebicidal activity against A. castellanii and N. fowleri . Furthermore, amoebae pretreated with 100 μg/mL peptide inhibited 35% and 53% A. castellanii and N. fowleri , while, at 250 μg/mL, 84% and 94% A. castellanii and N. fowleri failed to adhere to human cells. Amoeba-mediated cell cytopathogenicity assays revealed 31% and 42% inhibition at 100 μg/mL, while at 250 μg/mL 75% and 86% A. castellanii and N. fowleri were inhibited. Assays revealed inhibition of encystation in both A. castellanii (58% and 93%) and N. fowleri (73% and 97%) at concentrations of 100 and 250 μg/mL respectively. Importantly, tyrocidine-derived peptide depicted minimal cytotoxicity to human cells and, thus, may be a potential candidate in the rational development of a treatment regimen against free-living amoebae infections. Future studies are necessary to elucidate the in vivo effects of tyrocidine-derived peptide against these and other pathogenic amoebae of importance.

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“…The unique sequence folds into a β 6.3 ‐helical conformation, which dimerizes head‐to‐head to form a transmembrane ion channel in a lipid bilayer [18,19] . The resulting disruption of ion gradients is believed to contribute to the potent antibacterial [20,21] and cytotoxic activities of 1‐0 [10a,22] . Thus, the folding pattern and resulting biological activity of 1‐0 are precisely defined by the stereochemistry of the main chain.…”

Section: Resultsmentioning

confidence: 99%

¹⁸O/¹⁶O‐Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products

Takeuchi

Itoh

Inoue

2021

Chemistry An Asian Journal

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The demand for more efficient methods of establishing the undetermined stereochemistries of peptidic natural products continues unabated. A new method for microscale stereochemical determination was devised by integrating solid‐phase synthesis, split‐and‐mix randomization, 18O/16O‐encoding of d/l‐configurations, tandem mass spectrometry, and biological evaluation. Here we applied gramicidin A as the molecule for a blind test. Gramicidin A and its 31 diastereomers were randomly prepared in microgram scale with 18O/16O‐stereochemical encoding and subjected to MS/MS‐structural determination and cytotoxicity assay. Only the parent gramicidin A was selected from among the 32 stereoisomers, validating the high reliability of the present strategy.

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Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

Cited by 29 publications

References 62 publications

Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics

Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics

Novel Antiamoebic Tyrocidine-Derived Peptide against Brain-Eating Amoebae

¹⁸O/¹⁶O‐Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products

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Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

Cited by 29 publications

References 62 publications

Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics

Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics

Novel Antiamoebic Tyrocidine-Derived Peptide against Brain-Eating Amoebae

18O/16O‐Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products

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¹⁸O/¹⁶O‐Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products