New Delhi metallo-beta-lactamase facilitates the emergence of cefiderocol resistance in Enterobacter cloacae.

Cefiderocol is a promising novel siderophore cephalosporin for the treatment of multi-drug 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 show that the presence of the New-Delhi metallo-β-lactamase (NDM) facilitates the emergence of resistance via non-synonymous 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 implies that caution should be taken, when using cefiderocol for the treatment of infections caused by metallo-β-lactamase- producing bacteria.