Identification of ABC transporter Cdr1 inhibitors of Candida glabrata

Mohd Waseem; Shubhashis Das; Debarati Mondal; Anuj Kumari; Ritu Kulshreshtha; Jitendra K Thakur; Naidu Subbarao

doi:10.1016/j.abb.2024.110270

Identification of ABC transporter Cdr1 inhibitors of Candida glabrata

Arch Biochem Biophys. 2024 Dec 15:764:110270. doi: 10.1016/j.abb.2024.110270. Online ahead of print.

Authors

Mohd Waseem¹, Shubhashis Das², Debarati Mondal³, Anuj Kumari⁴, Ritu Kulshreshtha⁴, Jitendra K Thakur⁵, Naidu Subbarao⁶

Affiliations

¹ School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India; Plant Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
² Plant Mediator Lab, National Institute of Plant Genome Research, New Delhi, 110067, India; Plant Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
³ Plant Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
⁴ Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India.
⁵ Plant Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India. Electronic address: [email protected].
⁶ School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India. Electronic address: [email protected].

PMID: 39681305
DOI: 10.1016/j.abb.2024.110270

Abstract

Candida glabrata is one of the most common causes of invasive candidiasis. Rising treatment failures from resistance to current antifungal drugs highlight the need for new antifungals. Overexpression of efflux pump transporter genes is significantly associated with the development of multidrug resistance. In this study, we have identified novel and potential inhibitors of ABC transporter Cdr1 of Candida glabrata (CgCdr1) by employing high throughput virtual screening of large chemical datasets from five different chemical libraries (ZINC, DrugBank, ChemDiv antifungal, ChemDiv Kinases, and ChEMBL bioassay). As a result many molecules were predicted to have higher binding affinity toward the CgCdr1, in which a naturally occurring compound, pentagalloyl glucose, was identified to significantly reduce the growth of Candida glabrata with an IC₅₀ value of 16.97 ± 2.1 μM. Molecular dynamics studies showed stable binding of pentagalloyl glucose with CgCdr1 protein. In summary, our research identifies pentagalloyl glucose as a novel antifungal compound that has the potential to be used for inhibiting the growth of Candida glabrata.

Keywords: Antifungal; Molecular docking; Molecular dynamic simulation; Multidrug resistance; Pentagalloyl glucose.