Comparative Genome Analysis of Ciprofloxacin-ResistantPseudomonas aeruginosaReveals Genes Within Newly Identified High Variability Regions Associated With Drug Resistance Development

Abstract

The alarming rise of ciprofloxacin-resistant Pseudomonas aeruginosa has been reported in several clinical studies. Though the mutation of resistance genes and their role in drug resistance has been researched, the process by which the bacterium acquires high-level resistance is still not well understood. How does the genomic evolution of P. aeruginosa affect resistance development? Could the exposure of antibiotics to the bacteria enrich genomic variants that lead to the development of resistance, and if so, how are these variants distributed through the genome? To answer these questions, we performed 454 pyrosequencing and a whole genome analysis both before and after exposure to ciprofloxacin. The comparative sequence data revealed 93 unique resistance strain variation sites, which included a mutation in the DNA gyrase subunit A gene. We generated variationdistribution maps comparing the wild and resistant types, and isolated 19 candidates from three discrete resistance-associated high variability regions that had available transposon mutants, to perform a ciprofloxacin exposure assay. Of these region candidates with transposon disruptions, 79% (15/19) showed a reduction in the ability to gain high-level resistance, suggesting that genes within these high variability regions might enrich for certain functions associated with resistance development.

Mycoplasmas and Their Antibiotic Resistance: The Problems and Prospects in Controlling Infections

“…2 ). These data were obtained for Pseudomonas aeruginosa in connection with the development of resistance to certain antibiotics, including ciprofloxacin [ 87 , 96 , 109 ]. The development of resistance to antimicrobials in various bacterial species proved to be associated with changes not only in the targets of these drugs, but also in many genes and proteins involved in the processes of energy production, transport, and protective mechanisms, as well as in virulence.…”

PA3225 Is a Transcriptional Repressor of Antibiotic Resistance Mechanisms in Pseudomonas aeruginosa

“…PA3228 was previously suggested to be important for the possible development of planktonic ciprofloxacin resistance ( 38 ). Here, we demonstrated that the ΔPA3228 deletion mutants (especially in the ΔPA3225 background) were more susceptible than the parental wild-type and ΔPA3225 strains to a broad range of antibiotics, thereby suggesting a role for PA3228 in intrinsic drug resistance.…”