Active Starvation Responses Mediate Antibiotic Tolerance in Biofilms and Nutrient-Limited Bacteria

TLDR

Antibiotic tolerance rises in nutrient‑limited bacteria, largely because starvation‑induced growth arrest reduces target activity. Tolerance is driven by the stringent response, which lowers oxidative stress in starving cells. Active starvation responses, not passive growth arrest, mediate tolerance; disabling the stringent response sensitizes biofilms to multiple antibiotics and improves treatment efficacy.

Abstract

Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.