Evolution of resistance to a tricyclic pyrimidoindole DNA gyrase/topoisomerase inhibitor in Escherichia coli and Acinetobacter baumannii is driven by upregulation of efflux machinery.
Semen A LeynJames E KentJaime E ZlamalMarinela L ElaneMaarten VercruysseAndrei L OstermanPublished in: bioRxiv : the preprint server for biology (2023)
The significance of this work is in assessing the mutational landscape and evolutionary dynamics of resistance acquisition against a novel antibiotic, GP6. This approach showed that, in contrast to ciprofloxacin (CIP), a previously studied a canonical DNA gyrase/topoisomerase-targeting clinical antibiotic, evolution of GP6-resistance is driven largely by early and most prominent mutational events leading to upregulation of efflux machinery. An identified asymmetry in cross-resistance of evolved GP6- vs CIP-resistant clones provides important guidelines for rational selection of potential treatment regimens. This study illustrates the utility of the established morbidostat-based comparative resistomics workflow for the assessment of new drug candidates and clinical antibiotics.
Keyphrases
- acinetobacter baumannii
- escherichia coli
- pseudomonas aeruginosa
- drug resistant
- circulating tumor
- poor prognosis
- cell proliferation
- magnetic resonance
- signaling pathway
- single cell
- magnetic resonance imaging
- computed tomography
- dna methylation
- risk assessment
- genome wide
- clinical practice
- contrast enhanced
- circulating tumor cells