Sub-lethal concentrations of antibiotics increase mutation frequency in the cystic fibrosis pathogen Pseudomonas aeruginosa

Abstract

Approximately 80% of adult patients with cystic fibrosis (CF) become chronically infected with Pseudomonas aeruginosa and consequently require antibiotic therapy at intervals throughout their lives. Achieving lethal concentrations of antibiotics in the lung remains a challenge. Recent evidence from Escherichia coli and Staphylococcus aureus suggests that the generation of hydroxyl radicals by sublethal concentrations of antibiotics may induce mutagenesis and confer bacteria with resistance to a wide range of antimicrobials. As Ps. aeruginosa can persist for many years following colonization of the airways and during this time it is repeatedly exposed to bactericidal antibiotics, we tested whether its exposure to sublethal levels increases mutation frequency. We demonstrate that sublethal levels of three classes of bactericidal antibiotics commonly used against Ps. aeruginosa infections, β-lactams, aminoglycosides and quinolones lead to an increase in mutation frequency, varying between c. threefold increase with aminoglycosides and a c. 14-fold increase in mutation frequency with β-lactam antibiotics. These findings could be clinically significant because exposure to sublethal concentrations of antibiotics during chronic infection leading to increased mutation frequency may facilitate adaptive radiation of pathogenic bacteria in the heterogeneous environment of the CF lung.

Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

“…Additionally, oxidation of DNA and free nucleotides can induce mismatched pairing, mutagenesis, and DSBs (Cadet, 2003; Foti et al, 2012; Haghdoost et al, 2006). We detected significantly elevated rates of DSBs that support previous reports that detected higher mutagenesis rates and DNA damage during antibiotic exposure (Dwyer et al, 2012; Foti et al, 2012; Kohanski et al, 2010a; Méhi et al, 2014; Nair et al, 2013). …”

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

“…Due to location of the bacteria in zones where the concentration of systemically administered antibiotics are sub-optimal, the role of subinhibitory concentrations of antibiotics for the occurrence of bacterial heterogeneity has also been studied [230][231][232][233], showing that exposure to sub-MIC concentrations led to occurrence and selection of resistant bacteria to several classes of antibiotics unrelated to the drug of exposure, suggesting a general increase in mutability as mechanism.…”

The phenotypic evolution of Pseudomonas aeruginosa populations changes in the presence of subinhibitory concentrations of ciprofloxacin

“…The immediate responses of P. aeruginosa to subinhibitory concentrations of ciprofloxacin have been investigated in several studies that reported enhancement in the frequency of mutation leading to carbapenem (especially meropenem) resistance (Tanimoto et al, 2008), reduction of swimming and swarming motilities (Linares et al, 2006) and increase in spontaneous mutation frequencies (Nair et al, 2013). Transcriptional responses of P. aeruginosa to subinhibitory and inhibitory concentrations of ciprofloxacin demonstrated the induction or repression of hundreds of genes (Brazas et al, 2007;Brazas & Hancock, 2005;Cirz et al, 2006).…”