Molecular mechanisms underlying meropenem tolerance in Acinetobacter baumannii

Abstract

**Please note that the full text is embargoed until 02/01/2026** The emergence and proliferation of Gram-negative bacterial infections has become a serious public health concern due to their rapid rise of resistant to all the clinically available antibiotics. The increasing incidence of bacterial infections has prioritized the invention of new therapeutics to prevent the antibiotic treatment failure. Typically, Gram-negative bacteria use several defensive strategies such as modification of the cell envelope to escape the lethal effects of bactericidal antibiotics. Carbapenem beta-lactam considered last resort antibiotic to treat Gram-negative bacteria infections, while they are considered first line prescription against nosocomial pathogen Acinetobacter baumannii (denoted as Ab). Beside resistance, the susceptible populations of Ab show high tolerance to carbapenem antibiotic meropenem, which is an understudied potential contributor of treatment failure. Like Enterobacteriaceae, beta-lactam tolerance in Ab largely relies on the formation of cell wall deficient spheroplast like structure. However, how bacteria maintain its structural integrity without cell wall is poorly understood. Here we uncovered the molecular determinants that drive meropenem tolerance in Ab. We showed both outer membrane integrity and peptidoglycan (PG) maintenance genes are required for maintaining bacterial fitness during meropenem insult. Notably, PG recycling plays critical role for this extended survival. Additionally, we found PG recycling promotes cell elongation in Ab. Together, these finding emphasizes that both outer membrane rigidity and PG recycling is vital for maintaining cell homeostasis in Ab.