Systematic investigation of resistance evolution to common antibiotics reveals conserved collateral responses across common human pathogens

Mari Rodriguez de Evgrafov, Marius Faza, Konstantinos Asimakopoulos, Morten O- A. Sommer*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

As drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will increasingly be relied upon to treat infections and to slow the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism's collateral response to a wide variety of antibiotics. Results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. However, little is known about the extent of evolutionary conservation of these responses across species. We sought to address this knowledge gap by performing a systematic resistance evolution study of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) under uniform growth conditions using five clinically relevant antibiotics with diverse modes of action. Evolved lineages were analyzed for collateral effects and the molecular mechanisms behind the observed phenotypes. Fourteen universal cross-resistance and two global collateral sensitivity relationships were found among the lineages. Genomic analyses revealed drug dependent divergent and conserved evolutionary trajectories amongst the pathogens. Our findings suggest that collateral responses may be preserved across species. These findings may help extend the contribution of previous collateral network studies in the development of treatment strategies to address the problem of antibiotic resistance.
Original languageEnglish
Article numbere01273-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number1
Number of pages16
ISSN0066-4804
DOIs
Publication statusPublished - 2021

Keywords

  • Human pathogens
  • Resistance evolution
  • Antibiotic resistance
  • Collateral sensitivity
  • Cross-resistance
  • Drug resistance evolution

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