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

Li, Xiaoting; Zhao, Dongmei; Li, Weina; Sun, Jichao; Zhang, Xiuying

doi:10.3390/ijms23010197

Cited by 16 publications

(6 citation statements)

References 165 publications

(201 reference statements)

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“…NDM-positive strains are usually resistant to most of antimicrobial agents, due to coexistence of other resistance mechanisms ( Nordmann et al., 2011 ), leading to a variety of infections that are associated with high mortality ( Guducuoglu et al., 2017 ). Since NDM-1 was first identified in clinical isolates in India in 2008 ( Yong et al., 2009 ), 31 variants have been reported worldwide, representing a significant challenge for public health and clinical management ( Moellering, 2010 ; Dortet et al., 2014 ; Li et al., 2021 ). Of these, NDM-13 is a variant that has two amino acid substitutions (D95N and M154L) compared with NDM-1, resulting in the increased hydrolytic activity against cefotaxime ( Shrestha et al., 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Emergence of a Salmonella Rissen ST469 clinical isolate carrying blaNDM-13 in China

Huang

Zeng

et al. 2022

Front. Cell. Infect. Microbiol.

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New Delhi metallo-β-lactamase-13 (NDM-13) is an NDM variant that was first identified in 2015 and has not been detected in Salmonella species prior to this study. Here we describe the first identification of a Salmonella Rissen strain SR33 carrying blaNDM-13. The aim of this study was to molecularly characterize SR33’s antimicrobial resistance and virulence features as well as investigate the genetic environment of blaNDM-13. The Salmonella Rissen SR33 strain was isolated from a patient with fever and diarrhea. SR33 belonged to ST469, and it was found to be multidrug-resistant (MDR) and to carry many virulence genes. Phylogenetic analysis showed that SR33 shared a close relationship with most of the Chinese S. Rissen ST469 strains. blaNDM-13 was located in a transmissible IncI1 plasmid pNDM13-SR33. Sequence analysis of blaNDM-13-positive genomes downloaded from GenBank revealed that a genetic context (ΔISAba125-blaNDM-13-bleMBL-trpF) and a hybrid promoter (consisting of −35 sequences provided by ISAba125 and −10 sequences) were conserved. ISAba125 was truncated by IS1294 in three plasmids carrying blaNDM-13, including pNDM13-SR33. To our knowledge, this is the first report of blaNDM-13 carried by Salmonella. The emergence of blaNDM-13 in a clinical MDR S. Rissen ST469 strain highlights the critical need for monitoring and controlling the dissemination of blaNDM-13. blaNDM-13 carried by a transmissible IncI1 plasmid may result in an increased risk of blaNDM-13 transmission. IS1294 may be involved in the movement of blaNDM-13.

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Section: Introductionmentioning

confidence: 99%

Emergence of a Salmonella Rissen ST469 clinical isolate carrying blaNDM-13 in China

Huang

Zeng

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Irreversible inhibition of MBL (IMP-1) by 3-(3-mercaptopropionylsulfanyl) propionic acid pentafluorophenyl ester by binding to Lys224 and activity of ebselen against NDM-1 by binding to Cys221 are examples for such strategies (Kurosaki et al, 2005;Chiou et al, 2015). The major MBL inhibitors have been recently reviewed by Li et al (2022). Ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime-tazobactam, meropenemvaborbactam and imipenem-relebactam are the recently developed β-lactam-BLI combinations used to treat ESBL and carbapenemase producing bacterial pathogens (Yahav et al, 2020).…”

Section: β-Lactamase Inhibitors -Success Stories and Clinical Statusmentioning

confidence: 99%

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

et al. 2023

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β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The β-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, β-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of β-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of β-lactam antibiotics, which led to the discovery of β-lactamase inhibitors (BLIs) and other β-lactam potentiators. Although there are several successful β-lactam-β-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of β-lactamases have put the quest of new β-lactam potentiators beyond precedence. This review summarizes the success stories of β-lactamase inhibitors in use, prospective β-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel β-lactam potentiators. Furthermore, this review discusses the various challenges in taking these β-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.

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“…These molecules inhibit NDM-1 using different mechanisms, such as producing a covalent bond with enzyme pocket residues like Cys208 and con scating the Zinc ions. However, no molecules to date are recommended for clinical use due to e cacy and safety obstacles [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Rational design of novel compounds to serve as potential NDM-1 inhibitors using molecular docking, molecular dynamics simulation, and physicochemical studies

Salih

Ali

2023

Preprint

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New Delhi Metallo-β-lactamase enzyme (NDM-1) is an enzyme that hydrolyzes a wide range of β-lactam antibiotics, including most carbapenems, leading to antimicrobial resistance. The development of a novel NDM-1 inhibitor for use in combination with carbapenems may help to combat drug-resistant pathogens. Twenty compounds derived from naphthalene, thiazole, and sulfone derivatives were designed to inhibit bacterial NDM-1 and protect β-lactam antibiotics from enzyme attack. Two- and three-dimensional structures of the designed molecules were sketched using MarvinSketch, and a molecular docking protocol was used to identify potential inhibitor(s) of the NDM-1 target protein using AMDock v 1.5.2. The binding free energy of each compound against NDM-1 was determined and the drug-likeness properties of the designed molecules were assessed using SwissADME. Two compounds with the highest ΔGbinding results, T008 and T016, were selected for further investigation using molecular dynamic (MD) simulations with the GROMACS simulation package (GROMACS 2020.4). The duration of each MD simulation was 100 ns. Both compounds had a significantly higher binding free energy than the positive control and other designed molecules, their MD simulations remained stable, they passed Lipinski’s rule of five, and were shown to have favorable physicochemical properties. The study outcomes can be used to inform synthesis and in vitro testing of the selected molecules.

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

Cited by 16 publications

References 165 publications

Emergence of a Salmonella Rissen ST469 clinical isolate carrying blaNDM-13 in China

Emergence of a Salmonella Rissen ST469 clinical isolate carrying blaNDM-13 in China

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

Rational design of novel compounds to serve as potential NDM-1 inhibitors using molecular docking, molecular dynamics simulation, and physicochemical studies

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