Apr 4, 2020

(p)ppGpp and malonyl-CoA set the pace for Staphylococcus aureus adaptation to FASII antibiotics and provide a basis for bi-therapy inhibition

BioRxiv : the Preprint Server for Biology
Mick WatsonAlexandra Gruss

Abstract

Fatty acid biosynthesis (FASII) enzymes have been considered as valid targets for antimicrobial drug development against the human pathogen Staphylococcus aureus. However, our findings showed that incorporation of compensatory host fatty acids confers FASII antibiotic adaptation that compromises prospective treatments. Adaptation to anti-FASII drugs is preceded by a non-replicative latency period. Here we investigated the factors that dictate the duration of latency prior to adaptation outgrowth, and identify stringent response as a regulator of both FASII and adaptation to FASII inhibition. We first show that (p)ppGpp induction inhibits malonyl-CoA synthesis, and constitutes a second regulator of FASII and phospholipid synthesis in S. aureus, in addition to the FapR repressor. We then show that anti-FASII treatment triggers transient (p)ppGpp induction during the anti-FASII latency phase, with a concomitant reduction of FapR regulon expression. This effect is reversed upon adaptive outgrowth. Using three different sensors, we give evidence that anti-FASII treatment shifts the distribution of malonyl-CoA between its interactants, FapR and FabD, increasing expression of phospholipid synthesis genes plsX and plsC during outgrowth...Continue Reading

  • References
  • Citations

References

  • We're still populating references for this paper, please check back later.
  • References
  • Citations

Citations

  • This paper may not have been cited yet.

Mentioned in this Paper

Nucleic Acid Sequencing
Medical Devices
Bio-Informatics
Sequencing
Pore
Pore Proteins
Analysis
Cheumatopsyche mickeli
Anisopodidae
Motivation

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Bioinformatics in Biomedicine (Preprints)

Bioinformatics in biomedicine incorporates computer science, biology, chemistry, medicine, mathematics and statistics. Discover the latest preprints on bioinformatics in biomedicine here.