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(p)ppGpp and malonyl-CoA set the pace for Staphylococcus aureus adaptation to FASII antibiotics and provide a basis for bi-therapy inhibition
- Authors :
- Pathania, Amit
Anba-Mondoloni, Jamila
Halpern, David
Dupont, Laƫtitia
Lamberet, Gilles
Trieu-Cuot, Patrick
Gloux, Karine
Gruss, Alexandra - Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- Fatty acid biosynthesis (FASII) enzymes have been considered as valid targets for antimicrobial drug development against the human pathogen Staphylococcus aureus . However, incorporation of host fatty acids confers FASII antibiotic adaptation that compromises prospective treatments. S. aureus adaptation to FASII inhibitors 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 show that in addition to the FapR repressor, (p)ppGpp induction inhibits malonyl-CoA synthesis, and constitutes a second regulator of FASII and phospholipid synthesis in S. aureus . 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. Results indicate that anti-FASII treatment shifts malonyl-CoA distribution between its interactants, FapR and FabD, increasing expression of phospholipid synthesis genes plsX and plsC during outgrowth. We conclude that (p)ppGpp pools dictate malonyl-CoA availability in S. aureus FASII regulation, and contribute to latency prior to anti-FASII adaptation. A combinatory approach, coupling a (p)ppGpp inducer and an anti-FASII, blocks S. aureus growth, opening perspectives for bi-therapy treatment.
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.sharebioRxiv..481dbbe9de9ae66e115fa391b149b625
- Full Text :
- https://doi.org/10.1101/2020.03.26.007567