Abstract

Background:The in vivo efficacy and mechanisms of matrine (MT) in reversing β-lactam resistance inE. coliremain unclear.Methods: β-lactam-resistantE. colistrains were treated with MT both in vitro and in a murine intestinal colonization model. Phenotypic changes (MIC, morphology, growth, biofilm, β-lactamase) were evaluated, and transcriptomic profiles were analyzed.Results: MT at sub-inhibitory concentrations significantly and concentration-dependently reduced the MICs of β-lactam-resistantE. colistrains by 2- to 32-fold in vitro. This reduction was also confirmed in vivo, and its magnitude became more pronounced as the number of doses increased. MT treatment dispersed bacterial aggregates and dissipated extracellular matrix, but did not alter the morphology of individual bacteria. At concentrations above 1024 μg/mL, MT significantly inhibited bacterial growth; lower concentrations (≤512 μg/mL) had no effect. Notably, MT inhibited biofilm formation and β-lactamase production both in vitro and in vivo.Conclusions:MT restored the susceptibility of β-lactam-resistantE. colito cefepime and cefquinome. This effect was associated with suppression of biofilm formation and β-lactamase production, which correlated with the downregulation of key genes (ycgR,pgaB,pgaD,blaTEMandblaCTX-M).