Collective antibiotic resistance occurs when populations of bacteria survive antibiotic treatments that are lethal to individual bacteria, which affects the efficacy of drug therapies. An important mechanism of collective resistance against widely used Formula: see text-lactams is the production of drug-degrading Formula: see text-lactamases. Here, we integrate experiments with mathematical modeling to understand the collective survival of Escherichia coli challenged with cefotaxime (CTX). At near-lethal CTX concentrations, we observe complex dynamics, involving initial biomass growth due to filamentation, followed by death, and subsequently growth recovery. We show that production of AmpC, a chromosomal Formula: see text-lactamase, is responsible for CTX degradation, allowing the resumption of cell division in surviving filaments. The detoxification of the environment proceeds through CTX hydrolysis by AmpC in the periplasm of intact cells, as well as extracellularly after cell lysis. Our model predicts the recovery time from molecular parameters, and quantifies the relative roles of periplasmic and extracellular degradation for two strains of E. coli that differ in the degree of privatization of AmpC hydrolysis. Our findings suggest that Formula: see text-lactam survival of bacterial infections depends on a combination of intra- and extracellular Formula: see text-lactamase activity, which will likely vary among isolates.
Gross et al. (Thu,) studied this question.