Contributions of intra- and extracellular antibiotic degradation to collective β-lactam survival

Abstract

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 β -lactams is the production of drug-degrading β -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 β -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 β -lactam survival of bacterial infections depends on a combination of intra- and extracellular β -lactamase activity, which will likely vary among isolates.