TY - JOUR T1 - (p)ppGpp and malonyl-CoA set the pace for <em>Staphylococcus aureus</em> adaptation to FASII antibiotics and provide a basis for bi-therapy inhibition JF - bioRxiv DO - 10.1101/2020.03.26.007567 SP - 2020.03.26.007567 AU - Amit Pathania AU - Jamila Anba-Mondoloni AU - David Halpern AU - Laƫtitia Dupont AU - Gilles Lamberet AU - Patrick Trieu-Cuot AU - Karine Gloux AU - Alexandra Gruss Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/04/2020.03.26.007567.abstract N2 - 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. ER -