Bacteriostatic lethality emerges from turgor-induced physiological stress

With new antibiotic discovery slowing, maximizing the efficacy of existing drugs is crucial. Bacteriostatic antibiotics are regarded as inferior to bactericidal drugs because they are thought to merely arrest growth without inflicting cellular damage and cell death. Contrary to conventional views, we show that bacteriostasis is a physiologically stressed state, which can be exploited to unmask its lethality. Through quantitative measurements and live-cell imaging, we found that translation inhibition by bacteriostatic antibiotics induces intracellular turgor pressure buildup by perturbing physiological balance in E. coli . This pressure manifests as osmotic swelling, leading to lysis in a subset of cells, while surviving cells depend on PBP1-mediated cell-wall repair, which alleviates mechanical strain. This protective mechanism led us to predict, and we experimentally confirmed, that inactivating PBP1 with a β-lactam amplifies the lethality of bacteriostatic drugs, challenging the general assumption of antagonism between bacteriostatic and bactericidal antibiotics. These findings show bacteriostasis as a physiologically unstable state and provide a systems-level framework for its lethality, enabling the rational design of optimized therapies.