Efforts towards the inhibitor design for New Delhi metallo-beta-lactamase (NDM-1)

Venkata, Kalyan C. Nagulapalli; Ellebrecht, Morgan; Tripathi, Siddharth

doi:10.1016/j.ejmech.2021.113747

Cited by 19 publications

(5 citation statements)

References 65 publications

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“…Hence, the identification of inhibitors against metallo‐β‐lactamases is highly urgent and represents the major challenge in the field of β‐lactamase inhibitor development. A great number of compounds such as thiols, thioesters, azolylthioacetamide, carboxylic acids, cyclic boronates and aspergillomarasmine A showed activity to inhibit metallo‐β‐lactamases by diverse mechanisms (King et al, 2014; Nagulapalli Venkata et al, 2021). Despite of the worldwide academic efforts, only a few metallo‐β‐lactamases inhibitors are close to clinical use.…”

Section: Discussionmentioning

confidence: 99%

Novel metallo‐β‐lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo‐lactamase‐1 (NDM‐1)‐harbouring bacteria

Guo

Liu

Yang

et al. 2023

British J Pharmacology

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Background and purposeThe production of metallo‐β‐lactamases (MBLs) is one of the major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost‐effective approach to fight infections caused by carbapenem resistant pathogens.Experimental approachThe nitrocefin hydrolysis assay was employed to screen potential NDM‐1 inhibitors from a commercially available U.S. Food and Drug Administration (FDA) ‐approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP‐MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time‐dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy.Key resultsTwelve FDA‐approved compounds were initially screened to neutralize the ability of NDM‐1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil (CAN) and nordihydroguaiaretic acid (NDGA) were further demonstrated to inhibit all tested MBLs, and showed an in vitro synergistic bactericidal effect with meropenem against MBLs‐producing bacteria. Dexrazoxane, embelin and CAN are metal ion chelating agents, while the inhibition of NDM‐1 by NDGA involves its direct binding with the active region of NDM‐1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models.Conclusions and implicationsOur observations indicated that dexrazoxane, embelin, CAN and NDGA are promising carbapenem adjuvants against MBLs‐positive carbapenem resistant bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

Novel metallo‐β‐lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo‐lactamase‐1 (NDM‐1)‐harbouring bacteria

Guo

Liu

Yang

et al. 2023

British J Pharmacology

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“…Good quality data are imperative for building a good performing predictive model. To this end and for avoiding any bias or flaws, a sequential approach was adopted,which included a research by keywords on devoted websites (PubMed© and SciFinder©), and the main scientific editors (ACS, Elsevier, RSC and Willey) as well as the study of the most recent reviews on the topic [ 10 , 41 , 42 ]. At this point, a methodology was established to prevent the introduction of duplicate compounds.…”

Section: Architecture/implementation/workflowmentioning

confidence: 99%

Discovering NDM-1 inhibitors using molecular substructure embeddings representations

Papastergiou

Azé

Bringay

et al. 2023

Journal of Integrative Bioinformatics

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NDM-1 (New-Delhi-Metallo-β-lactamase-1) is an enzyme developed by bacteria that is implicated in bacteria resistance to almost all known antibiotics. In this study, we deliver a new, curated NDM-1 bioactivities database, along with a set of unifying rules for managing different activity properties and inconsistencies. We define the activity classification problem in terms of Multiple Instance Learning, employing embeddings corresponding to molecular substructures and present an ensemble ranking and classification framework, relaying on a k-fold Cross Validation method employing a per fold hyper-parameter optimization procedure, showing promising generalization ability. The MIL paradigm displayed an improvement up to 45.7 %, in terms of Balanced Accuracy, in comparison to the classical Machine Learning paradigm. Moreover, we investigate different compact molecular representations, based on atomic or bi-atomic substructures. Finally, we scanned the Drugbank for strongly active compounds and we present the top-15 ranked compounds.

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“…The gene ( bla NDM-1 ) is readily transferred from one bacterium to another via horizontal gene transfer. 13 Such metallo-based resistant phenotype/genotype has been reported amongst Gram-negative enteric bacteria ( Klebsiella pneumonia, Pseudomonas aeruginosa, Escherichia coli, Morganella morganii, Acinetobacter baumannii , and Proteus mirabilis etc. ) globally with high endemicity in the USA and Greece.…”

Section: Introductionmentioning

confidence: 96%

Occurrence of New Delhi Metallo-Beta-Lactamase 1 Producing Enterococcus Species in Oghara Water Nexus: An Emerging Environmental Implications of Resistance Dynamics

Esegbuyota

Onohuean

Oyama³

2022

Microbiol�Insights

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Various members of the enteric bacteria in recent times are evolving diverse survival mechanisms for antibiotic therapy resulting in failure of treatment in infection and disease cases. The Enterococcus species are potential strains implicated in gastrointestinal tract infection and are recently evolving in the resistance mechanism. The study evaluates the occurrence of New Delhi Metallo-beta-lactamase 1 (NDM-1) amongst Enterococcus species using the phenotypic and genomic characterization of environmental strains in the Oghara water nexus. Presumptive isolates of Enterococcus species were retrieved from various sampled water sources and confirmed using polymerase chain reaction (PCR). Antibiotic susceptibility testing was conducted on confirmed isolates using Kirby-Bauer disk diffusion methods. The result reveals 63 genus isolates confirmed Enterococcus species, of which 42 (67%) were Enterococcus faecium, 15 (23%) were Enterococcus faecalis, and 6 (10%) were other Enterococcus species. Fourteen among the E. faecalis isolates show resistance to Ertapenem-EDTA, while 17 (44.8%) of the E. faecium show resistance to Ertapenem-EDTA to presumptively reveal their NDM-1 phenotype. The PCR detection of the NDM-1 gene further confirmed 23 (36.5%) isolates as positive genotypes amongst the isolates that previously showed presumptive NDM-1 phenotype. It was also observed that 10 (15.9%) of Enterococcus faecium members harbored the NDM-1 genotype, whereas 8 (12.7%) members of the Enterococcus faecalis harbored the NDM-1 genotype. The observation of such resistance determinants necessitates a call for the adroit application of relevant therapeutics in the management of related infections and an environmental health caution to prevent the spread of such resistance potential enteric bacteria pathogens.

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Efforts towards the inhibitor design for New Delhi metallo-beta-lactamase (NDM-1)

Cited by 19 publications

References 65 publications

Novel metallo‐β‐lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo‐lactamase‐1 (NDM‐1)‐harbouring bacteria

Novel metallo‐β‐lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo‐lactamase‐1 (NDM‐1)‐harbouring bacteria

Discovering NDM-1 inhibitors using molecular substructure embeddings representations

Occurrence of New Delhi Metallo-Beta-Lactamase 1 Producing Enterococcus Species in Oghara Water Nexus: An Emerging Environmental Implications of Resistance Dynamics

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