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.