Scientific Publications
Cefotaxime exposure selects mutations within the CA-domain of envZ which promote antibiotic resistance but repress biofilm formation in Salmonella
PLOS Pathogens
Cephalosporins are important beta lactam antibiotics but resistance can be mediated by various mechanisms including production of beta lactamase enzymes, changes in membrane permeability or active efflux. We used an evolution model to study how Salmonella adapts to sub-inhibitory concentrations of cefotaxime in planktonic and biofilm conditions, and characterised the mechanisms underpinning this adaptation. We found that Salmonella rapidly adapts to subinhibitory concentrations of cefotaxime via selection of multiple mutations within the CA-domain region of EnvZ. We showed that changes in this domain affect the ATPase activity of the enzyme and in turn impact OmpC, OmpF porin expression and hence membrane permeability leading to increased tolerance. Adaptation to cefotaxime through EnvZ also resulted in a significant cost to biofilm formation due to downregulation of curli. We assessed the role of the mutations identified on the activity of EnvZ by genetic characterisation, biochemistry and in silico analysis and confirmed that they are responsible for the observed phenotypes. We observed that sub-lethal cefotaxime exposure selected for heterogeneity in populations with only a subpopulation carrying mutations within EnvZ and being resistant to cefotaxime. Population structure and composition dynamically changed depending on the presence of the selection pressure, once selected, resistant sub-populations were maintained even in extended passage without drug.
PLOS Pathogens
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