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Area of Science:

  • Microbiology
  • Molecular Biology
  • Evolutionary Biology

Background:

  • Antibiotic resistance is a growing global health crisis, threatening the efficacy of existing and novel antimicrobial agents.
  • The development pipeline for new antibiotics faces challenges due to the potential for rapid evolution of resistance.

Purpose of the Study:

  • To investigate the in vitro emergence of resistance to novel antibiotic candidates compared with currently used antibiotics.
  • To assess the prevalence of resistance mechanisms in natural microbial populations and clinical isolates.
  • To identify factors influencing resistance development and propose criteria for effective antibiotic candidate development.

Main Methods:

  • Laboratory evolution experiments exposing priority Gram-negative pathogens (ESKAPE) to antibiotic candidates and in-use antibiotics.
  • Functional metagenomics to screen for mobile resistance genes in diverse environmental and clinical samples.
  • Comparative analysis of resistance development patterns and mechanisms.

Main Results:

  • Clinically relevant antibiotic resistance emerged within 60 days in key Gram-negative pathogens (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa).
  • Resistance mutations are frequently pre-existing in natural pathogen populations, suggesting selection of variants.
  • Mobile resistance genes targeting antibiotic candidates are widespread in clinical isolates, soil, and gut microbiomes.
  • Antibiotic candidates demonstrated similar susceptibility to resistance development as current antibiotics, with overlapping resistance mechanisms.
  • Specific antibiotic-strain combinations showed reduced propensity for resistance evolution, indicating potential for narrow-spectrum therapies.

Conclusions:

  • Antibiotic candidates face comparable resistance development risks as existing antibiotics.
  • The presence of pre-existing resistance genes in natural and clinical settings complicates the efficacy of new antimicrobial drugs.
  • Identifying antibiotic-strain combinations less prone to resistance is crucial for developing sustainable, effective antibacterial therapies.