Evolution of β-lactamase-mediated cefiderocol resistance

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Cefiderocol is a novel siderophore beta-lactam antibiotic designed to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria.
• Its structure offers improved stability against various beta-lactamases, including carbapenemases, making it a potential treatment option.

Purpose of the Study:

• To investigate the impact of cefiderocol on the development of resistance.
• To examine the evolution of key beta-lactamases (KPC-2, CTX-M-15, NDM-1, CMY-2, OXA-48) in response to cefiderocol exposure.

Main Methods:

• Utilized directed evolution with error-prone PCR and selective plating to study beta-lactamase evolution.
• Assessed cefiderocol susceptibility using microbroth dilution assays (MIC and IC50).

Main Results:

• Expression of KPC-2, CMY-2, CTX-M-15, and NDM-1 significantly reduced cefiderocol susceptibility (4- to 32-fold).
• As few as 1-2 mutations enabled beta-lactamases to evolve increased cefiderocol resistance (2- to 16-fold).
• Resistance development often led to collateral cross-resistance against ceftazidime and ceftazidime/avibactam.

Conclusions:

• Contemporary beta-lactamase genes can drive cefiderocol resistance development.
• Mutations in these genes allow enzymes to adapt to cefiderocol, potentially causing significant cross-resistance issues.