Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Area of Science:

• Microbiology
• Genetics
• Infectious Diseases

Background:

• Bloodstream infections, often fatal, are frequently caused by Enterobacterales.
• Amikacin and piperacillin/tazobactam are common treatments for bloodstream infections.
• Antibiotic resistance necessitates understanding resistance mechanisms and dissemination.

Purpose of the Study:

• To investigate the dissemination and mechanism of a transposon conferring resistance to amikacin and piperacillin/tazobactam in Enterobacterales.
• To determine the clinical impact of this resistance mechanism on treatment outcomes.

Main Methods:

• Analysis of gene cassettes within an ancestral integron.
• Identification of IS26-mediated transposition events.
• Study of bloodstream infection isolates from 769 patients across three hospitals.
• Investigation of enzyme production, promoter mutations, and transposon copy number.

Main Results:

• A transposon, derived from an ancestral integron and IS26, disseminates widely among Enterobacterales.
• This transposon encodes AAC(6 extprime)-Ib-cr and OXA-1, conferring resistance to amikacin and piperacillin/tazobactam, respectively.
• Simultaneous resistance to both antibiotics is driven by increased enzyme production via promoter mutation or, more commonly, increased transposon copy number.
• This resistance pattern can leave only meropenem as a treatment option.

Conclusions:

• The identified transposon is a significant driver of multidrug resistance in Enterobacterales causing bloodstream infections.
• Understanding the mechanisms of resistance (promoter mutation, copy number variation) is crucial for predicting treatment failure.
• Stratifying patients for meropenem or piperacillin/tazobactam therapy based on resistance profiles may improve outcomes and mitigate the emergence of carbapenem resistance.