NDM-9 resistance to taniborbactam

• Published in: The Lancet infectious diseases 2023-04, Vol.23 (4), p.401-402
• Main Authors: Le Terrier, Christophe, Gruenig, Virginia, Fournier, Claudine, Nordmann, Patrice, Poirel, Laurent
• Format: Article
• Language: English
• Subjects: Amides; Amino acid substitution; Amino acids; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; beta-Lactamases - genetics; Borinic Acids; Carbapenems; Carboxylic Acids; Cefepime; Commercialization; Drug Resistance, Multiple, Bacterial; E coli; Enzymes; Glutamic acid; Gram-negative bacteria; Humans; Infectious diseases; Inhibitors; Metallo-β-lactamase; Metallography; Microbial Sensitivity Tests; Multidrug resistance; β-Lactam antibiotics
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(23)00069-5

Acquired resistance to carbapenems in Gram-negative bacteria is mostly related to acquisition of carbapenem-hydrolysing β-lactamases, among which metallo-β-lactamases (MBLs) are of crucial concern because they substantially hydrolyse all β-lactam antibiotics, except monobactams.1 MBLs of the New Delhi MBL (NDM) group are the most frequently identified acquired carbapenemases worldwide, and they are not inactivated by currently commercialised β-lactamase inhibitors.2 Therefore, MBLs inhibitors are urgently needed, and considerable efforts have been made during the past decade to design and develop them.3 Taniborbactam, also known as VNRX-5313, belongs to the family of cyclic boronate β-lactamase inhibitors and is a promising MBL inhibitor. Taniborbactam has substantial inhibitory action against MBLs (except IMP enzymes) and inhibits all four β-lactamase classes.4 The cefepime–taniborbactam combination is currently under clinical phase 3 evaluation (NCT03840148), and has already showed excellent performances when testing extensive collections of multidrug-resistant (and particularly carbapenem-resistant) Gram-negative isolates worldwide.5 In this study, we have assessed the in-vitro activity of cefepime–taniborbactam against different NDM-like-producing recombinant Escherichia coli strains, including a recombinant NDM-9. Notably, NDM-9 differs from NDM-1 by a single amino acid substitution (Glu152Lys), whereas NDM-5 and NDM-7 share the same glutamic acid residue at position 152 with NDM-1.6 Position 152 is located within a short loop connecting helix α4 and strand β8 in the NDM sequences, corresponding to the so-called omega loop, which is a key position in the three-dimensional structure of these enzymes.