Researchers uncover genetic pathways behind rising cefiderocol resistance

Acinetobacter baumannii is a bacteria which can become a virulent killer in health-care settings among severely ill patients. The germ has rapidly developed drug resistance to even last-line carbapenem drugs.

Now a group of Hackensack Meridian Center for Discovery and Innovation (CDI) scientists have found a way to understand how the germ is evolving - and how best to strategize a fight against it.

"Genetic Basis of Cefiderocol Resistance in Acinetobacter baumannii- Insights from Functional Genomics and Clinical Isolates," is authored by a group led by Kevin Josue Rome in the journal Microbiology Spectrum, published by the American Society for Microbiology.

While a new antibiotic called Cefiderocol was approved for use in 2019, the bacteria has already evolved to become resistant to it.

The CDI team of Rome, Barry Kreiswirth, Ph.D., and colleagues have produced a huge whole-genome look at the rise of this resistance - pointing the way to new strategies in staying ahead of the pathogen.

Previous studies have looked at single mechanisms of how resistance evolves, according to the paper.

The team this time around took a more holistic approach. They used genome-wide transposon mutagenesis together with genomic and phenotypic analysis of CFDC-resistant clinical isolates to generate a more comprehensive view of how resistance emerges.

"Our genome-wide transposon mutagenesis provided an unbiased framework to uncover previously underappreciated determinants of (cefiderocol) resistance," they write. "By defining how these pathways converge, this work provides a broader mechanistic framework for interpreting emerging resistance in clinical settings.

"These insights underscore the need for integrated surveillance strategies and highlight the biological complexity that must be considered to preserve the effectiveness of this last-line antibiotic," they conclude.

The authors add that further work on these mechanisms point the way toward preventing the rise of further resistance.