Bacterial Responses and Genome Instability Induced by Subinhibitory Concentrations of Antibiotics

Abstract

Nowadays, the emergence and spread of antibiotic resistance have become an utmost medical and economical problem. It has also become evident that subinhibitory concentrations of antibiotics, which pollute all kind of terrestrial and aquatic environments, have a non-negligible effect on the evolution of antibiotic resistance in bacterial populations. Subinhibitory concentrations of antibiotics have a strong effect on mutation rates, horizontal gene transfer and biofilm formation, which may all contribute to the emergence and spread of antibiotic resistance. Therefore, the molecular mechanisms and the evolutionary pressures shaping the bacterial responses to subinhibitory concentrations of antibiotics merit to be extensively studied. Such knowledge is valuable for the development of strategies to increase the efficacy of antibiotic treatments and to extend the lifetime of antibiotics used in therapy by slowing down the emergence of antibiotic resistance.

Keywords: antibiotics; mutagenesis; resistance; stress response.

Figure 1

Impact of antibiotics on bacterial population.

Figure 2

Schematic representation of how Escherichia coli cells modulate mutation rates in response to subinhibitory concentrations of bactericidal antibiotics. Bactericidal antibiotics, like ampicillin, induce ROS production by stimulating cellular respiratory activity. ROS damage all cellular macromolecules, thus promoting, for example, protein oxidation, DNA replication arrest and oxidation of dNTPs pool. In the presence of subinhibitory concentration of ampicillin, the amount of RpoS and PolIV proteins is increased, most likely because the ClpPX protease-chaperon complex, which degrades both RpoS and PolIV, becomes titrated by an increased amount of oxidized proteins. At the same time, the arrest of the DNA replication forks together with higher level of the PolIV error-prone DNA polymerase favors the incorporation of oxidized dNTPs into the DNA, which eventually results in generation of mutations. However, antibiotic-increased mutagenesis is possible only because the mismatch repair system is not able to repair all the PolIV-generated mutations in ampicillin treated cells. The reduction of mismatch repair activity in antibiotic-treated cells is mediated by SdsR, an RpoS-controlled small RNA, which interacts with the mutS mRNA [15].