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

Corral-Rodríguez, Noé Fabián; Moreno-Contreras, Valeria Itzel; Sierra-Campos, Erick; Valdez-Solana, Mónica; Cisneros-Martínez, Jorge; Téllez-Valencia, Alfredo; Avitia-Domínguez, Claudia

doi:10.3390/biom15081137

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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

by

Noé Fabián Corral-Rodríguez

^1,†,

Valeria Itzel Moreno-Contreras

^1,†

,

Erick Sierra-Campos

²

,

Mónica Valdez-Solana

²

,

Jorge Cisneros-Martínez

¹,

Alfredo Téllez-Valencia

^1,*

and

Claudia Avitia-Domínguez

^1,*

¹

Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitua S/N, Durango 34000, Mexico

²

Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango Campus Gómez Palacio, Avenida Artículo 123 S/N, Fracc. Filadelfia, Gómez Palacio 35010, Mexico

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Biomolecules 2025, 15(8), 1137; https://doi.org/10.3390/biom15081137

Submission received: 9 June 2025 / Revised: 31 July 2025 / Accepted: 4 August 2025 / Published: 6 August 2025

(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery: 2nd Edition)

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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.

Keywords: drug discovery; natural products; methicillin-resistant S. aureus; shikimate pathway; shikimate dehydrogenase

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MDPI and ACS Style

Corral-Rodríguez, N.F.; Moreno-Contreras, V.I.; Sierra-Campos, E.; Valdez-Solana, M.; Cisneros-Martínez, J.; Téllez-Valencia, A.; Avitia-Domínguez, C. Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies. Biomolecules 2025, 15, 1137. https://doi.org/10.3390/biom15081137

AMA Style

Corral-Rodríguez NF, Moreno-Contreras VI, Sierra-Campos E, Valdez-Solana M, Cisneros-Martínez J, Téllez-Valencia A, Avitia-Domínguez C. Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies. Biomolecules. 2025; 15(8):1137. https://doi.org/10.3390/biom15081137

Chicago/Turabian Style

Corral-Rodríguez, Noé Fabián, Valeria Itzel Moreno-Contreras, Erick Sierra-Campos, Mónica Valdez-Solana, Jorge Cisneros-Martínez, Alfredo Téllez-Valencia, and Claudia Avitia-Domínguez. 2025. "Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies" Biomolecules 15, no. 8: 1137. https://doi.org/10.3390/biom15081137

APA Style

Corral-Rodríguez, N. F., Moreno-Contreras, V. I., Sierra-Campos, E., Valdez-Solana, M., Cisneros-Martínez, J., Téllez-Valencia, A., & Avitia-Domínguez, C. (2025). Characterization of Natural Products as Inhibitors of Shikimate Dehydrogenase from Methicillin-Resistant Staphylococcus aureus: Kinetic and Molecular Dynamics Simulations, and Biological Activity Studies. Biomolecules, 15(8), 1137. https://doi.org/10.3390/biom15081137

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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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