Shared and Unique Evolutionary Trajectories to Ciprofloxacin Resistance in Gram-negative Bacterial Pathogens

摘要: The resistance to broad-spectrum antibiotic ciprofloxacin is detected in high rates for a wide range of bacterial pathogens. To investigate dynamics development we proposed comparative resistomics workflow three clinically relevant species Gram-negative bacteria: Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. We combined experimental evolution morbidostat with deep sequencing evolving populations time series that reveals both shared unique aspects evolutionary trajectories patterns. Representative clone characterization by MIC measurements enabled direct assessment mutations impact on the extent acquired drug resistance. In all observed two-stage evolution: (1) early reaching 4-16-fold wildtype commonly as result single DNA gyrase target genes (gyrA or gyrB) (2) additional genetic alterations affecting transcriptional control efflux machinery secondary (DNA topoisomerase parC parE). ImportanceThe challenge spreading calls systematic efforts develop more "irresistible" drugs based deeper understanding mechanisms acquisition. address this challenge, have established approach which combines continuous culturing device, morbidostat, ultradeep microbial identify (mutations genome rearrangements) leading over Here report study bacteria (Escherichia aeruginosa), revealed species-specific landscape robust against important ciprofloxacin. addition specific findings, highlighting anticipated utility morbidostat-based genomic guide rational optimization treatment regimens current antibiotics novel minimized propensities.