Cefiderocol “under siege”? Understanding the rise of NDM-mediated resistance to novel agents

The global spread of antimicrobial resistance (AMR) underscores the critical need for the rapid development of new drugs. Particularly alarming is the surge in metallo-β-lactamases (MBLs) - broad spectrum enzymes able to inactivate penicillins, cephalosporins, and carbapenems. Cefiderocol (FDC), a siderophore-containing cephalosporin, was initially reported as resistant to MBL hydrolysis. Indeed, FDC has been designated as the preferred treatment for Gram-negative pathogens producing MBLs - with the most common MBLs of clinical concern belonging to the NDM, VIM, or IMP families. Regrettably, increasing reports of FDC resistance are emerging. Many of these events are linked to overexpression of NDM, sometimes coupled to alterations in iron transporters, challenging the notion of FDC being invulnerable to MBL hydrolysis. Herein, we demonstrate that NDM-1 and -5 are able to inactivate FDC efficiently, while VIM-2 and IMP-1 show impaired catalytic efficiency against this substrate. All these MBL enzymes form a reversible enzyme-product adduct with FDC, whose lifetime varies considerably among MBLs. In IMP-1 and VIM-2, this results in efficient enzyme inhibition. In contrast, NDM variants are poorly inhibited, eliciting efficient turnover rates. We propose a mechanistic explanation for FDC action that aligns with clinical findings suggesting NDMs contributing to FDC resistance. Based on these conclusions, we suggest caution when using this potent cephalosporin against NDM-producers. FDC paired with an NDM-inhibitor may be a strategy to preserve this important antibiotic.

Authors

Institutions

Publication Details

Journal
Chemical Science
Published
2025-01-01
DOI
https://doi.org/10.1039/d5sc02122g
Citations
11
Primary Topic
Antibiotic Resistance in Bacteria
Type
article
Field-Weighted Citation Impact
6.50

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Cefiderocol “under siege”? Understanding the rise of NDM-mediated resistance to novel agents

Robert A. Bonomo, Graciela Mahler, Krisztina M. Papp‐Wallace, Daisuke Ono et al.
11 citations
Chemical Science
Antibiotic Resistance in Bacteria
6.50
article

Cefiderocol “under siege”? Understanding the rise of NDM-mediated resistance to novel agents

Robert A. Bonomo, Graciela Mahler, Krisztina M. Papp‐Wallace, Daisuke Ono, Diego Martín Moreno, Pranita D. Tamma, Pablo E. Tomatis, Salvador I. Drusin, Guillermo Bahr, Alejandro J. Vila, María F. Mojica, Christopher R. Bethel, Magdalena Rodríguez Saravia, Brenda A Warecki
article en
11 citations

Abstract

The global spread of antimicrobial resistance (AMR) underscores the critical need for the rapid development of new drugs. Particularly alarming is the surge in metallo-β-lactamases (MBLs) - broad spectrum enzymes able to inactivate penicillins, cephalosporins, and carbapenems. Cefiderocol (FDC), a siderophore-containing cephalosporin, was initially reported as resistant to MBL hydrolysis. Indeed, FDC has been designated as the preferred treatment for Gram-negative pathogens producing MBLs - with the most common MBLs of clinical concern belonging to the NDM, VIM, or IMP families. Regrettably, increasing reports of FDC resistance are emerging. Many of these events are linked to overexpression of NDM, sometimes coupled to alterations in iron transporters, challenging the notion of FDC being invulnerable to MBL hydrolysis. Herein, we demonstrate that NDM-1 and -5 are able to inactivate FDC efficiently, while VIM-2 and IMP-1 show impaired catalytic efficiency against this substrate. All these MBL enzymes form a reversible enzyme-product adduct with FDC, whose lifetime varies considerably among MBLs. In IMP-1 and VIM-2, this results in efficient enzyme inhibition. In contrast, NDM variants are poorly inhibited, eliciting efficient turnover rates. We propose a mechanistic explanation for FDC action that aligns with clinical findings suggesting NDMs contributing to FDC resistance. Based on these conclusions, we suggest caution when using this potent cephalosporin against NDM-producers. FDC paired with an NDM-inhibitor may be a strategy to preserve this important antibiotic.

Chemical ScienceVol. 16(27)
Johns Hopkins University (US), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Universidad de la República de Uruguay (UY), Johns Hopkins Medicine (US), National University of Rosario (AR), Louis Stokes Cleveland VA Medical Center (US), VA Northeast Ohio Healthcare System (US), Instituto de Biología Molecular y Celular de Rosario (AR), University School (US), Centro Uruguayo de Imagenología Molecular (UY), Case Western Reserve University (US)
U.S. Department of Veterans Affairs, Office of Research and Development, Biomedical Laboratory Research and Development, VA Office of Research and Development, Shionogi, Universidad de la República Uruguay, Agencia Santafesina de Ciencia, Tecnología e Innovación, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, National Institutes of Health, Geriatric Research Education and Clinical Center, National Institute of Allergy and Infectious Diseases, NIH Clinical Center, Fondo para la Investigación Científica y Tecnológica, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 3%
Antibiotic Resistance in Bacteria
6.50
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.