Ampicillin-controlled glucose metabolism manipulates the transition from tolerance to resistance in bacteria

The mechanism(s) of how bacteria acquire tolerance and then resistance to antibiotics remains poorly under-stood. Here, we show that glucose abundance decreases progressively as ampicillin-sensitive strains acquire resistance to ampicillin. The mechanism involves that ampicillin initiates this event via targeting pts promoter and pyruvate dehydrogenase (PDH) to promote glucose transport and inhibit glycolysis, respectively. Thus, glucose fluxes into pentose phosphate pathway to generate reactive oxygen species (ROS) causing genetic mutations. Meanwhile, PDH activity is gradually restored due to the competitive binding of accumulated pyruvate and ampicillin, which lowers glucose level, and activates cyclic adenosine monophosphate (cAMP)/cAMP receptor protein (CRP) complex. cAMP/CRP negatively regulates glucose transport and ROS but enhances DNA repair, leading to ampicillin resistance. Glucose and Mn2+ delay the acquisition, providing an effective approach to control the resistance. The same effect is also determined in the intracellular pathogen Edwardsiella tarda. Thus, glucose metabolism represents a promising target to stop/delay the transition of tolerance to resistance.

Automated summary

The research reveals that as ampicillin-sensitive strains acquire resistance to ampicillin, the abundance of glucose progressively decreases. Ampicillin triggers the event by targeting pts promoter and pyruvate dehydrogenase, leading to increased glucose transport and inhibited glycolysis. This process results in the activation of pentose phosphate pathway, generating reactive oxygen species and causing genetic mutations. The competitive binding of accumulated pyruvate and ampicillin gradually restores pyruvate dehydrogenase activity, lowers glucose level, and activates cAMP/CRP complex, inhibiting glucose transport and reactive oxygen species but enhancing DNA repair, ultimately leading to ampicillin resistance. Glucose and Mn2+ delay the acquisition of resistance, providing a promising approach to control antibiotic resistance.