Non-Toxic and Ultra-Small Biosilver Nanoclusters Trigger Apoptotic Cell Death in Fluconazole-Resistant Candida albicans via Ras Signaling

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2019-01, Vol.9 (2), p.47
• Main Authors: Singh, Braj Raj, Gupta, Vijai Kumar, Deeba, Farah, Bajpai, Rajesh, Pandey, Vivek, Naqvi, Alim H, Upreti, Dalip Kumar, Gathergood, Nicholas, Jiang, Yueming, El Enshasy, Hesham A, Sholkamy, Essam Nageh, Mostafa, Ashraf A, Hesham, Abd El-Latif, Singh, Brahma N
• Format: Article
• Language: English
• Subjects: Algae; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial activity; Antimicrobial agents; Apoptosis; biosilver nanoclusters; Candida albicans; Candida albicans - cytology; Candida albicans - drug effects; Cell Death; Cell Survival - drug effects; DNA fragmentation; Drug resistance; Drug Resistance, Fungal - drug effects; Electrodes; Fluconazole; Fluconazole - chemistry; Fluconazole - pharmacology; fluconazole-resistant Candida albicans; Glycolysis; Infections; Infectious diseases; Lichens - chemistry; Lichens - metabolism; Membrane potential; Metal Nanoparticles - chemistry; Microorganisms; Microscopy; Mitochondrial DNA; Nanomaterials; Nanoparticles; Nanotechnology; Oxidative stress; Particle Size; Polyphenols; proteomics; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; Ras protein; Ras signaling pathway; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Silver; Silver - chemistry; Silver - metabolism; Spectrum analysis; Surface Properties; Toxicity
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom9020047

Silver-based nanostructures are suitable for many biomedical applications, but to be useful therapeutic agents, the high toxicity of these nanomaterials must be eliminated. Here, we biosynthesize nontoxic and ultra-small silver nanoclusters (rsAg@NCs) using metabolites of usnioid lichen (a symbiotic association of algae and fungi) that exhibit excellent antimicrobial activity against fluconazole (FCZ)-resistant that is many times higher than chemically synthesized silver nanoparticles (AgNPs) and FCZ. The rsAg@NCs trigger apoptosis via reactive oxygen species accumulation that leads to the loss of mitochondrial membrane potential, DNA fragmentation, chromosomal condensation, and the activation of metacaspases. The proteomic analysis clearly demonstrates that rsAg@NCs exposure significantly alters protein expression. Most remarkable among the down-regulated proteins are those related to glycolysis, metabolism, free radical scavenging, anti-apoptosis, and mitochondrial function. In contrast, proteins involved in plasma membrane function, oxidative stress, cell death, and apoptosis were upregulated. Eventually, we also established that the apoptosis-inducing potential of rsAg@NCs is due to the activation of Ras signaling, which confirms their application in combating FCZ-resistant . infections.