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Cefiderocol is a promising novel siderophore cephalosporin for the treatment of multidrug-resistant Gram-negative bacilli and with stability against degradation by metallo-β-lactamases. Nonetheless, the emergence of cefiderocol in metallo-β-lactamase-producing Enterobacterales during therapy has been reported on more than one occasion. To understand the underlying mechanisms and factors facilitating the resistance development, we conducted an in vitro evolution experiment using clinical E. cloacae isolates via serial passaging under cefiderocol pressure. In this study, we showed that the presence of the New Delhi metallo-β-lactamase (NDM) facilitates the emergence of resistance via nonsynonymous mutations of the CirA catecholate siderophore receptor. Inhibition of metallo-β-lactamase activity using dipicolinic acid prevented the emergence of cefiderocol-resistant mutants successfully. This finding …