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Front. Microbiol. | doi: 10.3389/fmicb.2019.00326

The Antimicrobials Anacardic Acid and Curcumin are Not-Competitive Inhibitors of Gram-positive Bacterial Pathogenic Glyceraldehyde-3-phosphate Dehydrogenase by a Mechanism Unrelated to Human C5a Anaphylatoxin Binding

 Sara G. Quevedo1, Javier Querol-García1, 2, Gara Sánchez-Barrón1, Marta Subias1, 3,  Àlex González-Alsina4, Virginia Franco-Hidalgo1,  Sebastián Albertí4,  Santiago Rodriguez De Cordoba1, 3,  Francisco J. Fernández1, 5* and  M. Cristina Vega1*
  • 1Centro de Investigaciones Biológicas (CIB), Spain
  • 2Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Spain
  • 3Center for Biomedical Research in the Network of Rare Diseases (CIBERER), Spain
  • 4Universitat de les Illes Balears, Spain
  • 5Abvance Biotech srl, Spain

The ubiquitous and highly abundant glycolytic enzyme D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pivotal for the energy and carbon metabolism of most organisms, including human pathogenic bacteria. For bacteria that depend mostly on glycolysis for survival, GAPDH is an attractive target for inhibitor discovery. The availability of high-resolution structures of GAPDH from various pathogenic bacteria is central to the discovery of new antibacterial compounds. We have determined the X-ray crystal structures of two new GAPDH enzymes from Gram-positive bacterial pathogens, Streptococcus pyogenes and Clostridium perfringens. These two structures, and the recent structure of Atopobium vaginae GAPDH, reveal details in the active site that can be exploited for the design of novel inhibitors based on naturally occurring molecules. Two such molecules, anacardic acid and curcumin, have been found to counter bacterial infection in clinical settings, although the cellular targets responsible for their antimicrobial properties remain unknown. We show that both anacardic acid and curcumin inhibit GAPDH from two bacterial pathogens through uncompetitive and noncompetitive mechanisms, suggesting GAPDH as a relevant pharmaceutical target for antibacterial development. Inhibition of GAPDH by anacardic acid and curcumin seems to be unrelated to the immune evasion function of pathogenic bacterial GAPDH, since neither natural compound interfere with binding to the human C5a anaphylatoxin.

Keywords: GAPDH – glyceraldehyde 3-phospate dehydrogenase, Atopobium vaginae, Streptococcus pyogenes, Clostridium perfringens, Anacardic acid, Curcumin, Complement - immunological terms, enzyme inhibition, X-ray crystallography

Received: 13 Aug 2018; Accepted: 07 Feb 2019.

Edited by:

Octavio L. Franco, Universidade Católica de Brasília, Brazil

Reviewed by:

Claus Schneider, Vanderbilt University, United States
Jason J. Paxman, La Trobe Institute for Molecular Science, La Trobe University, Australia  

Copyright: © 2019 Quevedo, Querol-García, Sánchez-Barrón, Subias, González-Alsina, Franco-Hidalgo, Albertí, Rodriguez De Cordoba, Fernández and Vega. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Francisco J. Fernández, Centro de Investigaciones Biológicas (CIB), Madrid, 28040, Madrid, Spain, fjfernandez@abvance.com
Dr. M. Cristina Vega, Centro de Investigaciones Biológicas (CIB), Madrid, 28040, Madrid, Spain, cristina.vega@strubicib.org