Exploring the druggable proteome of Candida species through comprehensive computational analysis

• Published in: Genomics (San Diego, Calif.) Calif.), 2021-03, Vol.113 (2), p.728-739
• Main Authors: Mukherjee, Shuvechha, Kundu, Indra, Askari, Mehdi, Barai, Ram Shankar, Venkatesh, K.V., Idicula-Thomas, Susan
• Format: Article
• Language: English
• Subjects: amino acids; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; azoles; bioavailability; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - metabolism; Candida tropicalis; candidiasis; carbon metabolism; Computational Biology - methods; computer simulation; Diterpenes - chemistry; Diterpenes - pharmacology; Drug Discovery - methods; Drug Repositioning - methods; drugs; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; genes; genomics; Metabolic Flux Analysis - methods; Network analysis; polyenes; prioritization; Protein Binding; protein-protein interactions; proteome; Proteome - chemistry; Proteome - genetics; Proteome - metabolism; secondary metabolites; Software; Subtractive genomics; Systems biology; Target identification pipeline
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2020.12.040

Candida albicans and non-albicans Candida spp. are major cause of systemic mycoses. Antifungal drugs such as azoles and polyenes are not efficient to successfully eradicate Candida infection owing to their fungistatic nature or low bioavailability. Here, we have adopted a comprehensive computational workflow for identification, prioritization and validation of targets from proteomes of Candida albicans and Candida tropicalis. The protocol involves identification of essential drug-target candidates using subtractive genomics, protein-protein interaction network properties and systems biology based methods. The essentiality of the novel metabolic and non-metabolic targets was established by performing in silico gene knockouts, under aerobic as well as anaerobic conditions, and in vitro drug inhibition assays respectively. Deletion of twelve genes that are involved in amino acid, secondary metabolite, and carbon metabolism showed zero growth in metabolic model under simulated conditions. The algorithm, used in this study, can be downloaded from http://pbit.bicnirrh.res.in/offline.php and executed locally. •Novel metabolic and non-metabolic targets identified from C. albicans and C. tropicalis•Computational workflow integrated into a standalone tool for target discovery•Drug repurposing of retapamulin against novel target YmL9 in Candida spp.•Metabolic flux balance analysis identifies 12 essential targets in Candida spp.