High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development.

Antifungal Agents / pharmacology Phosphotransferases (Alcohol Group Acceptor) / genetics Pantothenic Acid / chemistry Fungi
Aspergillus fumigatus Saccharomyces cerevisiae antifungals drug susceptibility pantothenate kinase vitamin B5

Journal

Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697

Informations de publication

Date de publication:
03 11 2022
Historique:
received: 13 12 2021
revised: 28 07 2022
accepted: 01 09 2022
pubmed: 28 9 2022
medline: 9 11 2022
entrez: 27 9 2022
Statut: ppublish

Résumé

Fungal infections are the leading cause of mortality by eukaryotic pathogens, with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid emergence of multidrug-resistant fungal isolates highlights the urgent need for new drugs with new mechanisms of action. In fungi, pantothenate phosphorylation, catalyzed by PanK enzyme, is the first step in the utilization of pantothenic acid and coenzyme A biosynthesis. In all fungi sequenced so far, this enzyme is encoded by a single PanK gene. Here, we report the crystal structure of a fungal PanK alone as well as with high-affinity inhibitors from a single chemotype identified through a high-throughput chemical screen. Structural, biochemical, and functional analyses revealed mechanisms governing substrate and ligand binding, dimerization, and catalysis and helped identify new compounds that inhibit the growth of several Candida species. The data validate PanK as a promising target for antifungal drug development.

Identifiants

DOI: 10.1016/j.str.2022.09.001 PMID: 36167065 PMC: PMC10042587
pubmed: 36167065
pii: S0969-2126(22)00354-9
doi: 10.1016/j.str.2022.09.001
pmc: PMC10042587
mid: NIHMS1876713
pii:
doi:

Substances chimiques

Antifungal Agents 0
pantothenate kinase EC 2.7.1.33
Phosphotransferases (Alcohol Group Acceptor) EC 2.7.1.-
Pantothenic Acid 19F5HK2737

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1494-1507.e6

Subventions

Organisme : NIAID NIH HHS
ID : HHSN272201700059C
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI153100
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI123321
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI138139
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI152220
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests C.B.M. is the founder of Curatix, which focuses on the development of anti-infectives. The fungal PanK inhibitors described in this study are covered by a patent application filed by Yale University. All of the other authors declare no competing interests.

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Auteurs

Shalev Gihaz (S)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Peter Gareiss (P)

Yale Center for Molecular Discovery, Yale West Campus, West Haven, CT 06516, USA.

Jae-Yeon Choi (JY)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Isaline Renard (I)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Anasuya Chattopadhyay Pal (AC)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Yulia Surovsteva (Y)

Yale Center for Molecular Discovery, Yale West Campus, West Haven, CT 06516, USA.

Joy E Chiu (JE)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Jose Thekkiniath (J)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Mark Plummer (M)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

William Hungerford (W)

Yale Center for Molecular Discovery, Yale West Campus, West Haven, CT 06516, USA.

Micaela L Montgomery (ML)

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Alanah Hosford (A)

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Emily M Adams (EM)

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Jorge D Lightfoot (JD)

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

David Fox (D)

Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109, USA; UCB Pharma, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.

Kayode K Ojo (KK)

Center for Emerging & Re-emerging Infectious Disease, Division of Allergy & Infectious Disease, Department of Medicine, University of Washington, Seattle, WA 98109, USA.

Bart L Staker (BL)

Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109, USA.

Kevin Fuller (K)

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Choukri Ben Mamoun (C)

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: choukri.benmamoun@yale.edu.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antifongiques › High-resolution crystal structure and chemical...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Phosphotransferases (Alcohol Group Acceptor) › High-resolution crystal structure and chemical...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Alanine › bêta-Alanine › Acide pantothénique › High-resolution crystal structure and chemical...
questionsmedicales.fr › Eucaryotes › Champignons › High-resolution crystal structure and chemical...