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
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 fo...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-02-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.00326/full |
| _version_ | 1818160582450216960 |
|---|---|
| author | Sara Gómez Javier Querol-García Gara Sánchez-Barrón Marta Subias Marta Subias Àlex González-Alsina Virginia Franco-Hidalgo Sebastián Albertí Santiago Rodríguez de Córdoba Santiago Rodríguez de Córdoba Francisco J. Fernández M. Cristina Vega |
| author_facet | Sara Gómez Javier Querol-García Gara Sánchez-Barrón Marta Subias Marta Subias Àlex González-Alsina Virginia Franco-Hidalgo Sebastián Albertí Santiago Rodríguez de Córdoba Santiago Rodríguez de Córdoba Francisco J. Fernández M. Cristina Vega |
| author_sort | Sara Gómez |
| collection | DOAJ |
| description | 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 non-competitive 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. |
| first_indexed | 2024-12-11T16:04:10Z |
| format | Article |
| id | doaj.art-e00b8250695743a9beb16b516e0b8969 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-11T16:04:10Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-e00b8250695743a9beb16b516e0b89692022-12-22T00:59:15ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-02-011010.3389/fmicb.2019.00326419122The 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 BindingSara Gómez0Javier Querol-García1Gara Sánchez-Barrón2Marta Subias3Marta Subias4Àlex González-Alsina5Virginia Franco-Hidalgo6Sebastián Albertí7Santiago Rodríguez de Córdoba8Santiago Rodríguez de Córdoba9Francisco J. Fernández10M. Cristina Vega11Center for Biological Research, Spanish National Research Council, Madrid, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainCIBER de Enfermedades Raras, Madrid, SpainInstitut Universitari d’Investigació en Ciències de la Salut, University of the Balearic Islands, Mallorca, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainInstitut Universitari d’Investigació en Ciències de la Salut, University of the Balearic Islands, Mallorca, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainCIBER de Enfermedades Raras, Madrid, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainCenter for Biological Research, Spanish National Research Council, Madrid, SpainThe 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 non-competitive 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.https://www.frontiersin.org/article/10.3389/fmicb.2019.00326/fullGAPDH – glyceraldehyde-3-phosphate dehydrogenaseStreptococcus pyogenesClostridium perfringensanacardic acidcurcumincomplement – immunological term |
| spellingShingle | Sara Gómez Javier Querol-García Gara Sánchez-Barrón Marta Subias Marta Subias Àlex González-Alsina Virginia Franco-Hidalgo Sebastián Albertí Santiago Rodríguez de Córdoba Santiago Rodríguez de Córdoba Francisco J. Fernández M. Cristina Vega 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 Frontiers in Microbiology GAPDH – glyceraldehyde-3-phosphate dehydrogenase Streptococcus pyogenes Clostridium perfringens anacardic acid curcumin complement – immunological term |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | GAPDH – glyceraldehyde-3-phosphate dehydrogenase Streptococcus pyogenes Clostridium perfringens anacardic acid curcumin complement – immunological term |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.00326/full |
| work_keys_str_mv | AT saragomez theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT javierquerolgarcia theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT garasanchezbarron theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT martasubias theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT martasubias theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT alexgonzalezalsina theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT virginiafrancohidalgo theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT sebastianalberti theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT santiagorodriguezdecordoba theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT santiagorodriguezdecordoba theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT franciscojfernandez theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT mcristinavega theantimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT saragomez antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT javierquerolgarcia antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT garasanchezbarron antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT martasubias antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT martasubias antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT alexgonzalezalsina antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT virginiafrancohidalgo antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT sebastianalberti antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT santiagorodriguezdecordoba antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT santiagorodriguezdecordoba antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT franciscojfernandez antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding AT mcristinavega antimicrobialsanacardicacidandcurcuminarenotcompetitiveinhibitorsofgrampositivebacterialpathogenicglyceraldehyde3phosphatedehydrogenasebyamechanismunrelatedtohumanc5aanaphylatoxinbinding |