Enzymatic activity of PBP1B is required for growth rate-independent ppGpp-mediated resistance to PBP2 inhibitors in <i>E. coli</i>

Antimicrobial resistance is an increasing global health threat, but its underlying molecular mechanisms remain incompletely understood. This work clarifies ppGpp's role in mediating antibiotic resistance in <i>Escherichia coli</i>. Elevated levels of ppGpp caused resistance to β-lactam antibiotics targeting the cell wall synthesis enzyme PBP2. Resistance required transcriptional regulation by ppGpp and enzymatic activity of the cell wall enzyme PBP1B. ppGpp overproduction was found to increase expression of the PBP1B activator lpoB. Because ppGpp levels are controlled by nutritional conditions, this work suggests that nutritional availability may impact antibiotic efficacy.