DNA repair functions are essential for bacterial stress defense but render antibiotic tolerant sub-populations susceptible to ciprofloxacin and gentamicin upon prolonged treatment

Abstract

The unresponsiveness of bacterial tolerant subpopulations to antibiotics has been attributed to physiological dormancy triggered by environmental stresses. In this work, we showed that protein and DNA synthesis activities in tolerant subpopulations that formed during nutrient starvation remained at a high level and only dropped gradually during the course of six days-starvation. Interestingly, upon decline of these activities, the tolerant subpopulations became susceptible to antibiotics that target protein and DNA synthesis, which was found to be required to support DNA repair functions essential for prolonged survival of the tolerant subpopulation. The increasing susceptibility of the bacterial tolerant subpopulation to antibiotics was also due to diminishing energy production, antioxidant defense and efflux functions, which resulted in weakening defense and further inhibition of synthesis and functions of DNA repair and other defense proteins. These findings confirm that bacterial tolerant subpopulations remain physiological active, and open new opportunities for combating bacterial tolerance with existing antibiotics.