ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro

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.