NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

Abstract

New Delhi metallo-β-lactamase (NDM) is a metallo-β-lactamase able to hydrolyze almost all β-lactams. Twenty-four NDM variants have been identified in >60 species of 11 bacterial families, and several variants have enhanced carbapenemase activity. Klebsiella pneumoniae and Escherichia coli are the predominant carriers of bla_NDM, with certain sequence types (STs) (for K. pneumoniae, ST11, ST14, ST15, or ST147; for E. coli, ST167, ST410, or ST617) being the most prevalent. NDM-positive strains have been identified worldwide, with the highest prevalence in the Indian subcontinent, the Middle East, and the Balkans. Most bla_NDM-carrying plasmids belong to limited replicon types (IncX3, IncFII, or IncC). Commonly used phenotypic tests cannot specifically identify NDM. Lateral flow immunoassays specifically detect NDM, and molecular approaches remain the reference methods for detecting bla_NDM Polymyxins combined with other agents remain the mainstream options of antimicrobial treatment. Compounds able to inhibit NDM have been found, but none have been approved for clinical use. Outbreaks caused by NDM-positive strains have been reported worldwide, attributable to sources such as contaminated devices. Evidence-based guidelines on prevention and control of carbapenem-resistant Gram-negative bacteria are available, although none are specific for NDM-positive strains. NDM will remain a severe challenge in health care settings, and more studies on appropriate countermeasures are required.

Keywords: Acinetobacter; Enterobacteriaceae; NDM; carbapenem resistance; carbapenemase; metalloenzymes.

FIG 1

NDM-1 amino acid sequence and NDM variants. The annotation of the NDM amino acid sequence is adopted from data reported under UniProt accession no. C7C422. Signal peptides of NDM-1 are framed with red lines. α-Helices, β-strands, and turns are indicated as black spirals and blue and orange lines, respectively. Amino acids at active sites of NDM-1 are highlighted in boldface type, and the zinc binding residues are highlighted in yellow. The lipidation box is highlighted in green. Two numbering systems for the amino acids are shown: numbering according to the standard number scheme of MBLs is shown in purple above the amino acid sequence, while numbering from the translation of NDM enzymes is shown in black below the sequence. Amino acid substitutions compared with NDM-1 are labeled in red, with the variant names shown in parentheses. NDM-18 has a tandem repeat of 5 amino acids (QRFGD), which is underlined.

FIG 2

Worldwide distribution of NDM-positive strains of the Enterobacteriaceae. Countries (Egypt, India, Pakistan, Serbia, and UAE) with evidence showing a prevalence of NDM-positive strains among the Enterobacteriaceae of ≥5% are indicated in red, while countries with reports of NDM-positive strains but without evidence of a ≥5% prevalence are shown in light brown. Countries without reports or data on NDM-positive strains are indicated in white.

FIG 3

Worldwide distribution of the replicon types of bla_NDM-carrying plasmids in Enterobacteriaceae. Detailed information about the distribution of the replicon types of bla_NDM-carrying plasmids is available in Table 3 and Data Set S2 in the supplemental material.

FIG 4

Examples of genetic contexts and mobilization mechanisms of bla_NDM. (A) Tn125 formed by two copies of ISAba125. (B) Composite transposon formed by two copies of IS26. (C) Composite transposon formed by two copies of IS903. orf, open reading frame. (D) Element formed by two copies of the TIME. (E) Composite transposon formed by two copies of IS3000. (F) Genetic contexts containing ISCR1. This element is also flanked by two copies of IS26. The plasmid names and GenBank accession numbers are shown. Δ represents truncated genes or elements.