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Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies

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Title: Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies
Authors: Noé Fabián Corral-Rodríguez, Valeria Itzel Moreno-Contreras, Erick Sierra-Campos, Mónica Valdez-Solana, Jorge Cisneros-Martínez, Alfredo Téllez-Valencia, Claudia Avitia-Domínguez
Source: Biomolecules, Vol 15, Iss 8, p 1137 (2025)
Publisher Information: MDPI AG, 2025.
Publication Year: 2025
Collection: LCC:Microbiology
Subject Terms: drug discovery, natural products, methicillin-resistant S. aureus, shikimate pathway, shikimate dehydrogenase, Microbiology, QR1-502
Description: Antibiotic resistance is considered to be one of the most complex health obstacles of our time. Methicillin-resistant Staphylococcus aureus (MRSA) represents a global health challenge due to its broad treatment resistance capacity, resulting in high mortality rates. The shikimate pathway (SP) is responsible for the biosynthesis of chorismate from glycolysis and pentose phosphate pathway intermediates. This pathway plays a crucial role in producing aromatic amino acids, folates, ubiquinone, and other secondary metabolites in bacteria. Notably, SP is absent in humans, which makes it a specific and potential therapeutic target to explore for discovering new antibiotics against MRSA. The present study characterized in vitro and in silico natural products as inhibitors of the shikimate dehydrogenase from methicillin-resistant S. aureus (SaSDH). The results showed that, from the set of compounds studied, phloridzin, rutin, and caffeic acid were the most potent inhibitors of SaSDH, with IC50 values of 140, 160, and 240 µM, respectively. Furthermore, phloridzin showed a mixed-type inhibition mechanism, whilst rutin and caffeic acid showed non-competitive mechanisms. The structural characterization of the SaSDH–inhibitor complex indicated that these compounds interacted with amino acids from the catalytic site and formed stable complexes. In biological activity studies against MRSA, caffeic acid showed an MIC of 2.2 mg/mL. Taken together, these data encourage using these compounds as a starting point for developing new antibiotics based on natural products against MRSA.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2218-273X
Relation: https://www.mdpi.com/2218-273X/15/8/1137; https://doaj.org/toc/2218-273X
DOI: 10.3390/biom15081137
Access URL: https://doaj.org/article/b2c141d0efb041fb891968999aeaea58
Accession Number: edsdoj.b2c141d0efb041fb891968999aeaea58
Database: Directory of Open Access Journals
Description
Abstract:Antibiotic resistance is considered to be one of the most complex health obstacles of our time. Methicillin-resistant Staphylococcus aureus (MRSA) represents a global health challenge due to its broad treatment resistance capacity, resulting in high mortality rates. The shikimate pathway (SP) is responsible for the biosynthesis of chorismate from glycolysis and pentose phosphate pathway intermediates. This pathway plays a crucial role in producing aromatic amino acids, folates, ubiquinone, and other secondary metabolites in bacteria. Notably, SP is absent in humans, which makes it a specific and potential therapeutic target to explore for discovering new antibiotics against MRSA. The present study characterized in vitro and in silico natural products as inhibitors of the shikimate dehydrogenase from methicillin-resistant S. aureus (SaSDH). The results showed that, from the set of compounds studied, phloridzin, rutin, and caffeic acid were the most potent inhibitors of SaSDH, with IC50 values of 140, 160, and 240 µM, respectively. Furthermore, phloridzin showed a mixed-type inhibition mechanism, whilst rutin and caffeic acid showed non-competitive mechanisms. The structural characterization of the SaSDH–inhibitor complex indicated that these compounds interacted with amino acids from the catalytic site and formed stable complexes. In biological activity studies against MRSA, caffeic acid showed an MIC of 2.2 mg/mL. Taken together, these data encourage using these compounds as a starting point for developing new antibiotics based on natural products against MRSA.
ISSN:2218273X
DOI:10.3390/biom15081137