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Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors.

Publication ,  Journal Article
Parsons, JB; Frank, MW; Subramanian, C; Saenkham, P; Rock, CO
Published in: Proceedings of the National Academy of Sciences of the United States of America
September 2011

The rationale for the pursuit of bacterial type 2 fatty acid synthesis (FASII) as a target for antibacterial drug discovery in Gram-positive organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. The regulation of FASII by extracellular fatty acids was examined in Staphylococcus aureus and Streptococcus pneumoniae, representing two important groups of pathogens. Both bacteria use the same enzymatic tool kit for the conversion of extracellular fatty acids to acyl-acyl carrier protein, elongation, and incorporation into phospholipids. Exogenous fatty acids completely replace the endogenous fatty acids in S. pneumoniae but support only 50% of phospholipid synthesis in S. aureus. Fatty acids overcame FASII inhibition in S. pneumoniae but not in S. aureus. Extracellular fatty acids strongly suppress malonyl-CoA levels in S. pneumoniae but not in S. aureus, showing a feedback regulatory system in S. pneumoniae that is absent in S. aureus. Fatty acids overcame either a biochemical or a genetic block at acetyl-CoA carboxylase (ACC) in S. aureus, confirming that regulation at the ACC step is the key difference between these two species. Bacteria that possess a stringent biochemical feedback inhibition of ACC and malonyl-CoA formation triggered by environmental fatty acids are able to circumvent FASII inhibition. However, if exogenous fatty acids do not suppress malonyl-CoA formation, FASII inhibitors remain effective in the presence of fatty acid supplements.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2011

Volume

108

Issue

37

Start / End Page

15378 / 15383

Related Subject Headings

  • Streptococcus pneumoniae
  • Staphylococcus aureus
  • Pyrones
  • Phenotype
  • Mutation
  • Microbial Sensitivity Tests
  • Fatty Acids
  • Fatty Acid Synthesis Inhibitors
  • Fatty Acid Synthases
  • Benzofurans
 

Citation

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Parsons, J. B., Frank, M. W., Subramanian, C., Saenkham, P., & Rock, C. O. (2011). Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 108(37), 15378–15383. https://doi.org/10.1073/pnas.1109208108
Parsons, Joshua B., Matthew W. Frank, Chitra Subramanian, Panatda Saenkham, and Charles O. Rock. “Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors.Proceedings of the National Academy of Sciences of the United States of America 108, no. 37 (September 2011): 15378–83. https://doi.org/10.1073/pnas.1109208108.
Parsons JB, Frank MW, Subramanian C, Saenkham P, Rock CO. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 2011 Sep;108(37):15378–83.
Parsons, Joshua B., et al. “Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors.Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 37, Sept. 2011, pp. 15378–83. Epmc, doi:10.1073/pnas.1109208108.
Parsons JB, Frank MW, Subramanian C, Saenkham P, Rock CO. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 2011 Sep;108(37):15378–15383.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2011

Volume

108

Issue

37

Start / End Page

15378 / 15383

Related Subject Headings

  • Streptococcus pneumoniae
  • Staphylococcus aureus
  • Pyrones
  • Phenotype
  • Mutation
  • Microbial Sensitivity Tests
  • Fatty Acids
  • Fatty Acid Synthesis Inhibitors
  • Fatty Acid Synthases
  • Benzofurans