A Label-Free Cellular Proteomics Approach to Decipher the Antifungal Action of DiMIQ, a Potent Indolo[2,3- b ]Quinoline Agent, against Candida albicans Biofilms

• Published in: International journal of molecular sciences 2021-01, Vol.22 (1), p.108
• Main Authors: Zarnowski, Robert, Jaromin, Anna, Zagórska, Agnieszka, Dominguez, Eddie G, Sidoryk, Katarzyna, Gubernator, Jerzy, Andes, David R
• Format: Article
• Language: English
• Subjects: Alanine; antifungal; Antifungal activity; Arginine; Biofilms; Biosynthesis; Candida; Candida albicans; Carbohydrates; Cell walls; Deoxyribonucleic acid; DiMIQ; DNA; Drug resistance; Extracellular matrix; Fungicides; Glycine; Gram-positive bacteria; indoloquinolines; Infections; Isoleucine; Leucine; Medical equipment; Metabolic pathways; Metabolism; Metabolites; Nucleic acids; Nucleotides; Oxidation; Pathogens; Phenylalanine; Proteins; Proteomics; Public health; Quinoline; Ribosomal proteins; RNA transport; Serine; Translation; tRNA; Tryptophan; Tyrosine; Valine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22010108

forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5 -indolo[2,3- ]quinoline) was evaluated against biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, . Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated infections.