Detection of NDM-19, a novel variant of the New Delhi metallo-β-lactamase with increased carbapenemase activity under zinc-limited conditions, in Switzerland

Mancini, Stefano; Keller, Peter M.; Greiner, Michael; Bruderer, Vera; Imkamp, Frank

doi:10.1016/j.diagmicrobio.2019.06.003

Cited by 12 publications

(14 citation statements)

References 17 publications

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“…Variant NDM-7 (NDM-1 D126N M150aL) presented increased MICs by ≥2-fold only for various carbapenems vs NDM-1, while another report found identical MICs for carbapenems for cells expressing NDM-7 vs those producing NDM-4 (NDM-1 M150aL) . Increases in MICs for certain cephalosporins were also later reported for strains expressing NDM-5 and NDM-7 vs NDM-1, and both NDM-7 and the related triple mutant NDM-19 (NDM-1 D126N M150aL A248V) were reported to confer resistance levels that were 2–4 binary dilutions higher than NDM-1 for cefepime and various carbapenems . While NDM-19 was observed to confer similar resistance levels than NDM-7 under standard conditions, MICs for cells expressing the former enzyme were higher in Zn(II)-depleted media.…”

Section: Mbls B1 B2 B3: Folding Evolution Superfamily Active Sites An...mentioning

confidence: 71%

“…487 Increases in MICs for certain cephalosporins were also later reported for strains expressing NDM-5 and NDM-7 vs NDM-1, 488 and both NDM-7 and the related triple mutant NDM-19 (NDM-1 D126N M150aL A248V) were reported to confer resistance levels that were 2− 4 binary dilutions higher than NDM-1 for cefepime and various carbapenems. 489 While NDM-19 was observed to confer similar resistance levels than NDM-7 under standard conditions, MICs for cells expressing the former enzyme were higher in Zn(II)-depleted media. Meanwhile, NDM-4 (NDM-1 M150aL) was found to increase MICs for imipenem and ertapenem by 2-fold with respect to NDM-1, 490 and an about 4-fold increment in meropenem and imipenem MICs was also observed for NDM-14 (NDM-1 D126G), while values for other β-lactams were outside the measured range.…”

Section: Representative Mbls: Main Enzymes Families Of Each Subclassmentioning

confidence: 93%

“…A248V substitution, located in the C-terminal region in alleles 6, 15, 19, and 27, reduces the flexibility of this region (and α3 region) in the apoenzyme, thereby limiting proteolysis by Prc (González et al, submitted). The M150aL and A248V substitutions seem to act independently of the genetic background: similar K d values were obtained for NDM-4 (M150aL) and NDM-15 (M150aL, A248V), and a similar increase in tolerance to Zn(II) restriction was observed when comparing NDM-6 (A248V) vs NDM-1 and NDM-19 (NDM-7 A248V) vs NDM-7 . Alleles combining these substitutions, such as NDM-15 (M150aL, A248V), are those showing the best performance under Zn(II) limiting conditions.…”

Section: Zn(ii) Homeostasis At the Host–pathogen Interface: Stability...mentioning

confidence: 99%

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Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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Antimicrobial resistance is one of the major problems in current practical medicine. The spread of genes coding for resistance determinants among bacteria challenges the use of approved antibiotics, narrowing the options for treatment. Resistance to carbapenems, last resort antibiotics, is a major concern. Metallo-β-lactamases (MBLs) hydrolyze carbapenems, penicillins, and cephalosporins, becoming central to this problem. These enzymes diverge with respect to serine-β-lactamases by exhibiting a different fold, active site, and catalytic features. Elucidating their catalytic mechanism has been a big challenge in the field that has limited the development of useful inhibitors. This review covers exhaustively the details of the active-site chemistries, the diversity of MBL alleles, the catalytic mechanism against different substrates, and how this information has helped developing inhibitors. We also discuss here different aspects critical to understand the success of MBLs in conferring resistance: the molecular determinants of their dissemination, their cell physiology, from the biogenesis to the processing involved in the transit to the periplasm, and the uptake of the Zn(II) ions upon metal starvation conditions, such as those encountered during an infection. In this regard, the chemical, biochemical and microbiological aspects provide an integrative view of the current knowledge of MBLs.

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Section: Mbls B1 B2 B3: Folding Evolution Superfamily Active Sites An...mentioning

confidence: 71%

Section: Representative Mbls: Main Enzymes Families Of Each Subclassmentioning

confidence: 93%

Section: Zn(ii) Homeostasis At the Host–pathogen Interface: Stability...mentioning

confidence: 99%

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Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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“…Which is in agreement with [8] showing resistance >3-4 dilution increases in MIC values for two or more antibiotics in zinc-depleted condition of NDM-4, 8, 7, 15. A233V, in turn, was not only a stabilizing substitution, not affecting zinc-binding abilities [7], but also appeared to further increase the carbapenemase activity under zinclimiting growth conditions [24]. The D130N amino acid change also presented in NDM-29, 7, 19.…”

Section: Functional Analysis Of Bla Ndm-29mentioning

confidence: 93%

Emergence of Hybrid Resistance and Virulence Plasmids Harboring New Delhi Metallo-β-Lactamase in Klebsiella pneumoniae in Russia

Starkova

Lazareva²,

Avdeeva

et al. 2021

Antibiotics

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The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a new threat to healthcare. In this study, we analyzed nine CR-hvKp isolates of different sequence-types (ST) recovered from patients with nosocomial infections in two hospitals in Saint Petersburg. Whole-genome sequencing showed that eight of them harbored large mosaic plasmids carrying resistance to carbapenems and hypervirulence simultaneously, and four different types of hybrid plasmids were identified. BLAST analysis showed a high identity with two hybrid plasmids originating in the UK and Czech Republic. We demonstrated that hybrid plasmids emerged due to the acquisition of resistance genes by virulent plasmids. Moreover, one of the hybrid plasmids carried a novel New Delhi metallo-beta-lactamase (NDM) variant, differing from NDM-1 by one amino acid substitution (D130N), which did not provide significant evolutionary advantages compared to NDM-1. The discovery of structurally similar plasmids in geographically distant regions suggests that the actual distribution of hybrid plasmids carrying virulence and resistance genes is much wider than expected.

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“…NDM-19 (D130N, M154L, and A233V) is a derivative of NDM-7 (D130N and M154L). Under zinc-restricted growth conditions, compared to NDM-1 or NDM-7, NDM-19 shown is less sensitive to carbapenems and cephalosporins [ 89 ]. Therefore, the stress caused by zinc depletion may be the major driving force for the evolution of NDM enzymes [ 61 , 69 ].…”

Section: Ndm-1 Variants and Global Distributionmentioning

confidence: 99%

Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants

Zhao

et al. 2021

IJMS

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Multidrug bacterial resistance endangers clinically effective antimicrobial therapy and continues to cause major public health problems, which have been upgraded to unprecedented levels in recent years, worldwide. β-Lactam antibiotics have become an important weapon to fight against pathogen infections due to their broad spectrum. Unfortunately, the emergence of antibiotic resistance genes (ARGs) has severely astricted the application of β-lactam antibiotics. Of these, New Delhi metallo-β-lactamase-1 (NDM-1) represents the most disturbing development due to its substrate promiscuity, the appearance of variants, and transferability. Given the clinical correlation of β-lactam antibiotics and NDM-1-mediated resistance, the discovery, and development of combination drugs, including NDM-1 inhibitors, for NDM-1 bacterial infections, seems particularly attractive and urgent. This review summarizes the research related to the development and optimization of effective NDM-1 inhibitors. The detailed generalization of crystal structure, enzyme activity center and catalytic mechanism, variants and global distribution, mechanism of action of existing inhibitors, and the development of scaffolds provides a reference for finding potential clinically effective NDM-1 inhibitors against drug-resistant bacteria.

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Detection of NDM-19, a novel variant of the New Delhi metallo-β-lactamase with increased carbapenemase activity under zinc-limited conditions, in Switzerland

Cited by 12 publications

References 17 publications

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Emergence of Hybrid Resistance and Virulence Plasmids Harboring New Delhi Metallo-β-Lactamase in Klebsiella pneumoniae in Russia

Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants

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