Genomic characterization of an NDM-9-producing $Acinetobacter\ baumannii$ clinical isolate and role of Glu152Lys substitution in the enhanced cefiderocol hydrolysis of NDM-9 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Frontiers in Microbiology Année : 2023

Genomic characterization of an NDM-9-producing $Acinetobacter\ baumannii$ clinical isolate and role of Glu152Lys substitution in the enhanced cefiderocol hydrolysis of NDM-9

Bogdan Iorga

Résumé

Here, we characterized the first French NDM-9-producing Acinetobacter baumannii isolate. A. baumannii 13A297, which belonged to the ST$^{Pas}$25 (international clone IC7), was highly resistant to β-lactams including cefiderocol (MIC > 32 mg/L). Whole genome sequencing (WGS) using both Illumina and Oxford Nanopore technologies revealed a 166-kb non-conjugative plasmid harboring a $bla_{NDM-9}$ gene embedded in a Tn 125 composite transposon. Complementation of E. coli DH5α and A. baumannii CIP70.10 strains with the pABEC plasmid carrying the $bla_{NDM-1}$ or bla$_{NDM-9}$ gene, respectively, resulted in a significant increase in cefiderocol MIC values (16 to > 256-fold), particularly in the NDM-9 transformants. Interestingly, steady-state kinetic parameters, measured using purified NDM-1 and NDM-9 (Glu152Lys) enzymes, revealed that the affinity for cefiderocol was 3-fold higher for NDM-9 ( $K_m$ = 53 μM) than for NDM-1 ( K$_m$ = 161 μM), leading to a 2-fold increase in catalytic efficiency for NDM-9 (0.13 and 0.069 μM$^{−1}$ .s$^{−1}$ , for NDM-9 and NDM-1, respectively). Finally, we showed by molecular docking experiments that the residue 152 of NDM-like enzymes plays a key role in cefiderocol binding and resistance, by allowing a strong ionic interaction between the Lys152 residue of NDM-9 with both the Asp223 residue of NDM-9 and the carboxylate group of the R1 substituent of cefiderocol.

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Bactériologie
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hal-04204833 , version 1 (14-09-2023)

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Susie Gaillot, Saoussen Oueslati, Jean-Baptiste Vuillemenot, Maxime Bour, Bogdan Iorga, et al.. Genomic characterization of an NDM-9-producing $Acinetobacter\ baumannii$ clinical isolate and role of Glu152Lys substitution in the enhanced cefiderocol hydrolysis of NDM-9. Frontiers in Microbiology, 2023, 14, pp.1253160. ⟨10.3389/fmicb.2023.1253160⟩. ⟨hal-04204833⟩
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