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Shui Liu, Yonglin Zhou, Xiaodi Niu, Tingting Wang, Jiyun Li, Zhongjie Liu, Jianfeng Wang, Shusheng Tang, Yang Wang, Xuming Deng
The emergence of plasmid-mediated New Delhi metallo-β-lactamase-1 (NDM-1) in carbapenem-resistant Gram-negative pathogens is an increasing clinical threat. Here we report the discovery of an NDM-1 inhibitor, magnolol, through enzyme inhibition screening. We showed that magnolol significantly inhibited NDM enzyme activity (IC50  = 6.47 µg/mL), and it restored the activity of meropenem against Escherichia coli ZC-YN3, an NDM-1-producing E. coli isolate, in in vitro antibacterial activity assays. Magnolol lacked direct antibacterial activity, but compared with meropenem alone, it reduced the MICs of meropenem against E...
December 2018: Cell Death Discovery
Martin Everett, Nicolas Sprynski, Alicia Coelho, Jérôme Castandet, Maëlle Bayet, Juliette Bougnon, Clarisse Lozano, David T Davies, Simon Leiris, Magdalena Zalacain, Ian Morrissey, Sophie Magnet, Kirsty Holden, Peter Warn, Filomena De Luca, Jean-Denis Docquier, Marc Lemonnier
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1...
March 12, 2018: Antimicrobial Agents and Chemotherapy
Inés Bado, Romina Papa Ezdra, Nicolás Cordeiro, Matilde Outeda, Leticia Caiata, Virginia García-Fulgueiras, Verónica Seija, Rafael Vignoli
OBJECTIVES: The objective of the present study was to characterise the mechanisms underlying quinolone and oxyimino-cephalosporin resistance in a Citrobacter freundii clinical isolate obtained from the ICU in Uruguay's University Hospital. METHODS: Citrobacter freundii strain CF638 was isolated from a urine culture. Identification and susceptibility testing were performed using the VITEK® 2 system, and MIC determination and disc diffusion assay, respectively. Resistance genes and mobile genetic elements were identified, by PCR and sequencing...
March 8, 2018: Journal of Global Antimicrobial Resistance
Hamid Solgi, Farzad Badmasti, Christian G Giske, Shadi Aghamohammad, Fereshteh Shahcheraghi
Objectives: Despite the fact that the blaOXA-48 and blaNDM-1 genes have successfully disseminated among Klebsiella pneumoniae isolates worldwide, outbreaks remain unidentified in Iran. Here we examined the molecular epidemiology of 96 carbapenem-resistant K. pneumoniae recovered from an Iranian hospital. Methods: A total of 96 non-replicate carbapenem-resistant K. pneumoniae were recovered from clinical specimens in a university hospital. Detection of ESBLs and carbapenemases produced by studied strains was performed using PCR and DNA sequencing...
March 6, 2018: Journal of Antimicrobial Chemotherapy
Zhihai Liu, Jiyun Li, Xiaoming Wang, Dejun Liu, Yuebin Ke, Yang Wang, Jianzhong Shen
The spread of carbapenem-resistant Enterobacteriaceae (CRE) mediated by New Delhi metallo-β-lactamase (NDM) poses a serious challenge to clinicians and has become a major public health concern. NDM has been evolving into variants that possess different hydrolysis activity toward antibiotics, so as to affect treatment strategy. In addition, very few studies on NDM variants have focused on animal-derived bacterial isolates. Our study reports a novel NDM variant, NDM-20, in an isolate of Escherichia coli CCD1 recovered from the food animal swine in China...
2018: Frontiers in Microbiology
Michael A Pfaller, Michael D Huband, Rodrigo E Mendes, Robert K Flamm, Mariana Castanheira
We evaluated meropenem-vaborbactam activity against 11,559 Enterobacteriaceae isolates, including 330 carbapenem-resistant phenotypes (CRE) and carbapenemase genotypes collected worldwide during 2015. Meropenem-vaborbactam (inhibitor at 8 mg/L) and comparators were susceptibility tested using reference broth microdilution methods. CRE isolates were screened for the presence of genes encoding carbapenemases and 292 (88.5%) of the CRE isolates carried these resistance genes. A total of 209 (63.3% of the CRE; 1...
March 3, 2018: International Journal of Antimicrobial Agents
Qiu E Yang, Siham Rajab Agouri, Jonathan Mark Tyrrell, Timothy Rutland Walsh
The occurrence of heavy metal resistance genes in multi-resistant Enterobacteriaceae possessing bla NDM-1 or bla CTX-M-15 genes were examined by PCR and S1-PFGE. When compared with clinical susceptible isolates (10.0-30.0%), the pcoA, merA, silC and arsA genes occurred with higher frequencies in bla NDM-1 (48.8-71.8%) and bla CTX-M-15 (19.4-52.8%) positive isolates, and they are mostly located on plasmids. Given the high association of metal resistance genes with multidrug resistant Enterobacteriaceae, the use of heavy metals in hospitals and the environment needs increased vigilance...
March 5, 2018: Antimicrobial Agents and Chemotherapy
Torunn Pedersen, John Osei Sekyere, Usha Govinden, Krishnee Moodley, Audun Sivertsen, Ørjan Samuelsen, Sabiha Yusuf Essack, Arnfinn Sundsfjord
Whole-genome sequence analyses revealed the presence of bla NDM-1 ( n =31), bla GES-5 ( n =8), bla OXA-232 ( n =1), or bla NDM-5 ( n =1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae isolated from in-patients in 10 private hospitals (2012-2013) in Durban, South Africa. Two novel NDM-1 encoding plasmids from Klebsiella pneumoniae were closed by PacBio sequencing. In p19-10_01 (IncFIB(K), 223.434 bp) bla NDM-1 was part of a Tn 1548 -like structure (16.276 bp) delineated by IS 26 The multireplicon plasmid p18-43_01 (IncR_1/IncFIB(pB171)/IncFII(Yp); 212...
March 5, 2018: Antimicrobial Agents and Chemotherapy
Qian Wang, Yuan He, Rui Lu, Wen-Ming Wang, Ke-Wu Yang, Hai Ming Fan, Yi Jin, G Michael Blackburn
The New Delhi metallo-β-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of β-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons...
March 5, 2018: Bioscience Reports
Philip Hinchliffe, Carol A Tanner, Anthony P Krismanich, Geneviève Labbé, Valerie J Goodfellow, Laura Marrone, Ahmed Desoky, Karina Calvopiña, Emily E Whittle, Fanxing Zeng, Matthew Avison, Niels C Bols, Stefan Siemann, James Spencer, Gary Igor Dmitrienko
There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs), enzymes which hydrolyze β-lactam antibiotics and confer resistance on Gram-negative bacteria. Here we present 6-phosphonomethylpyridine-2-carboxylates (PMPCs) as potent inhibitors of subclass B1 (IMP-1, VIM-2, NDM-1) and B3 (L1) MBLs. Inhibition followed a competitive, slow-binding model without an isomerization step (IC50 values 0.3 - 7.2 µM; Ki 0.03 - 1.5 µM). Minimum inhibitory concentration assays demonstrated potentiation of β-lactam (meropenem) activity against MBL-producing bacteria, including clinical isolates, at concentrations where eukaryotic cells remain viable...
February 27, 2018: Biochemistry
Zhu-Jun Yu, Sha Liu, Shu Zhou, Hui Li, Fan Yang, Ling-Ling Yang, Yong Wu, Li Guo, Guo-Bo Li
Rosmarinic acid (RA), a polyphenolic phytochemical, has broad-spectrum biological and pharmacological activity. A virtual target screening method termed IFPTarget combined with enzyme inhibition assays led to the identification of the clinically relevant metallo-β-lactamase (MBL) VIM-2 as one of unexploited targets of RA. The enzyme kinetic studies indicated that RA is a fully reversible, substrate-competitive VIM-2 inhibitor. The isothermal titration calorimetry (ITC) analyses revealed that the initial binding of RA to VIM-2 is mainly due to enthalpy contribution...
February 14, 2018: Bioorganic & Medicinal Chemistry Letters
Abid Ali, Mohd W Azam, Asad U Khan
New Delhi metallo β-lactamase-1 is one of the carbapenemases, causing hydrolysis of almost all β-lactamase antibiotics. Seventeen different NDM variants have been reported so far, they varied in their sequences either by single or multiple amino acid substitutions. Hence, it is important to understand its structural and functional relation. In the earlier studies role of active site residues has been studied but non-active site residues has not studied in detail. Therefore, we have initiated to further comprehend its structure and function relation by mutating some of its non-active site residues...
February 15, 2018: International Journal of Biological Macromolecules
Shuxian Wen, Donghua Feng, Zerong Lu, Junyan Liu, Brian M Peters, Hailing Tang, Danhong Su, Yong-Ping Lin, Ling Yang, Zhenbo Xu, Mark E Shirtliff, Dingqiang Chen
BACKGROUND: Carbapenem-resistant Gram-negative bacilli (GNB) have become an important cause of nosocomial infections of hospitalized patients. METHODS: To investigate the microbial infection patterns and molecular epidemiology characteristics of the carbapenem-resistant GNB isolates from a long-term hospitalized patient, antimicrobial susceptibility testing, phenotypic screening test for carbapenemase production, PCR screening and DNA sequencing of carbapenemase genes, repetitive extragenic palindromic sequence-based PCR (REP-PCR), multilocus sequencing typing (MLST) and genetic environment analysis were performed...
February 13, 2018: Microbial Pathogenesis
Juan Duan, Chuncai Hu, Jiafan Guo, Lianxian Guo, Jia Sun, Zuguo Zhao
The mechanism of substrate hydrolysis of New Delhi metallo-β-lactamase 1 (NDM-1) has been reported, but the process in which NDM-1 captures and transports the substrate into its active center remains unknown. In this study, we investigated the process of the substrate entry into the NDM-1 activity center through long unguided molecular dynamics simulations using meropenem as the substrate. A total of 550 individual simulations were performed, each of which for 200 ns, and 110 of them showed enzyme-substrate binding events...
February 14, 2018: Physical Chemistry Chemical Physics: PCCP
Siew Mun Liew, Ganeswrei Rajasekaram, Savithri D Puthucheary, Kek Heng Chua
OBJECTIVES: The increasing incidence of carbapenem-resistant Pseudomonas aeruginosa along with the discovery of novel metallo-β-lactamases (MBLs) is of concern. In this study, the isolation of Malaysian MBL-producing P. aeruginosa clinical strains was investigated. METHODS: Fifty-three P. aeruginosa clinical strains were isolated from different patients in Sultanah Aminah Hospital, Johor Bahru, Malaysia in 2015. Antimicrobial susceptibility test was conducted. Minimum inhibitory concentrations (MICs) of imipenem and meropenem were determined by Etest...
February 9, 2018: Journal of Global Antimicrobial Resistance
Nian-Zhi Ning, Xiong Liu, Fanghong Chen, Peng Zhou, Lihong Hu, Jian Huang, Zhan Li, Jie Huang, Tao Li, Hui Wang
The emergence and spread of carbapenemase in Gram-negative pathogens poses an enormous threat to global public health. New Delhi metallo-β-lactamase-1 (NDM-1) inactivates nearly every class of β-lactam antibiotics, including carbapenem; however, there is no clinically useful NDM-1 inhibitor. Embelin, an important ingredient in traditional herbal medicine, has anti-tumor effects. The current study is the first to discover and examine the inhibitory activity of embelin against β-lactamase NDM-1. The IC50 of embelin was 2...
2018: Frontiers in Microbiology
Fusun Can, Sirin Menekse, Pelin Ispir, Nazli Atac, Ozgur Albayrak, Tuana Demir, Doruk Can Karaaslan, Salih Nafiz Karahan, Mahir Kapmaz, Ozlem Kurt Azap, Funda Timurkaynak, Serap Simsek Yavuz, Seniha Basaran, Fugen Yoruk, Alpay Azap, Safiye Koculu, Nur Benzonana, Nathan A Lack, Mehmet Gönen, Onder Ergonul
Objectives: We describe the molecular characteristics of colistin resistance and its impact on patient mortality. Methods: A prospective cohort study was performed in seven different Turkish hospitals. The genotype of each isolate was determined by MLST and repetitive extragenic palindromic PCR (rep-PCR). Alterations in mgrB were detected by sequencing. Upregulation of pmrCAB, phoQ and pmrK was quantified by RT-PCR. mcr-1 and the genes encoding OXA-48, NDM-1 and KPC were amplified by PCR...
February 3, 2018: Journal of Antimicrobial Chemotherapy
Yafei Ye, Lijuan Xu, Yanping Han, Zhe Chen, Cailin Liu, Liang Ming
Carbapenemase-producing 'super bacteria', particularly NDM-1 and its variants, have become a major public health concern worldwide. The present study aimed to explore the molecular mechanism for carbapenem resistance of clinical Enterobacteriaceae isolates. Seventy-eight non-repeated Enterobacteriaceae strains resistant to any carbapenem were screened at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between December 2011 and December 2015. Outer membrane porin (OMP) proteins were detected using SDS-PAGE...
January 2018: Experimental and Therapeutic Medicine
G L Vanstone, S Woodhead, K Roulston, H Sharma, E Wey, E R Smith, D Mack, I Balakrishnan
PURPOSE: Carbapenemase-producing organisms (CPOs) can be resistant to almost all β-lactams and represent an increasing threat in healthcare facilities. Detection of these organisms in routine diagnostic laboratories is difficult; here we evaluate four commercially available CPO detection assays and assess their suitability for the clinical laboratory. METHODOLOGY: A panel of 95 clinical multidrug-resistant organisms (22 NDM, 24 OXA-48, 19 VIM, 4 OXA-23, 3 KPC, 4 NDM+OXA-48, 1 OXA23+NDM, 1 IMI, 1 IMP-1, 9 ESBL, 3 derepressed AmpC and 4 inducible AmpC producers) were tested by the RESIST-3 O...
February 2018: Journal of Medical Microbiology
Runming Wang, Tsz-Pui Lai, Peng Gao, Hongmin Zhang, Pak-Leung Ho, Patrick Chiu-Yat Woo, Guixing Ma, Richard Yi-Tsun Kao, Hongyan Li, Hongzhe Sun
Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors...
January 30, 2018: Nature Communications
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