Crystal Structure of New Delhi Metallo-β-lactamase Reveals Molecular Basis for Antibiotic Resistance

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2011 Jul 21

PMID 21774017

Citations 93

Authors

Dustin King

Natalie Strynadka

Affiliations

Soon will be listed here.

Abstract

β-Lactams are the most commonly prescribed class of antibiotics and have had an enormous impact on human health. Thus, it is disquieting that an enzyme called New Delhi metallo-β-lactamase-1 (NDM-1) can confer Enterobacteriaceae with nearly complete resistance to all β-lactam antibiotics including the carbapenams. We have determined the crystal structure of Klebsiella pneumoniae apo-NDM-1 to 2.1-Å resolution. From the structure, we see that NDM-1 has an expansive active site with a unique electrostatic profile, which we propose leads to a broader substrate specificity. In addition, NDM-1 undergoes important conformational changes upon substrate binding. These changes have not been previously observed in metallo-β-lactamase enzymes and may have a direct influence on substrate recognition and catalysis.

Citing Articles

Phytosterols as inhibitors of New Delhi metallo-β-lactamase (NDM-1): an in silico study.

Rahman M, Ahsan M, Rehman M, Alajmi M, Khan M Mol Divers. 2024; .

PMID: 39514168 DOI: 10.1007/s11030-024-11020-6.

Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors.

Alkhatabi H, Alatyb H Pharmaceuticals (Basel). 2024; 17(9).

PMID: 39338345 PMC: 11435111. DOI: 10.3390/ph17091183.

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant .

Abdulaal W, Alhakamy N, Asseri A, Radwan M, Ibrahim T, Okbazghi S Front Pharmacol. 2024; 15:1366459.

PMID: 38533260 PMC: 10963397. DOI: 10.3389/fphar.2024.1366459.

Fluorescently Modified NDM-1: A Versatile Drug Sensor for Rapid β-Lactam Antibiotic and Inhibitor Screening.

Chung S, Tam S, Wong W, So P, Cheong W, Mak C ACS Omega. 2024; 9(8):9161-9169.

PMID: 38434906 PMC: 10906033. DOI: 10.1021/acsomega.3c08117.

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae.

Abdel-Halim M, El-Ganiny A, Mansour B, Yahya G, Latif H, Askoura M BMC Microbiol. 2024; 24(1):67.

PMID: 38413891 PMC: 10898048. DOI: 10.1186/s12866-024-03214-7.

References

Kumarasamy K, Toleman M, Walsh T, Bagaria J, Butt F, Balakrishnan R . Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010; 10(9):597-602. PMC: 2933358. DOI: 10.1016/S1473-3099(10)70143-2. View

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

Materon I, Beharry Z, Huang W, Perez C, Palzkill T . Analysis of the context dependent sequence requirements of active site residues in the metallo-beta-lactamase IMP-1. J Mol Biol. 2004; 344(3):653-63. DOI: 10.1016/j.jmb.2004.09.074. View

Bootsma H, Aerts P, Posthuma G, Harmsen T, Verhoef J, Van Dijk H . Moraxella (Branhamella) catarrhalis BRO beta-lactamase: a lipoprotein of gram-positive origin?. J Bacteriol. 1999; 181(16):5090-3. PMC: 94001. DOI: 10.1128/JB.181.16.5090-5093.1999. View

Bush K . Alarming β-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol. 2010; 13(5):558-64. DOI: 10.1016/j.mib.2010.09.006. View

Walsh T, Weeks J, Livermore D, Toleman M . Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis. 2011; 11(5):355-62. DOI: 10.1016/S1473-3099(11)70059-7. View

Garcia-Saez I, Docquier J, Rossolini G, Dideberg O . The three-dimensional structure of VIM-2, a Zn-beta-lactamase from Pseudomonas aeruginosa in its reduced and oxidised form. J Mol Biol. 2007; 375(3):604-11. DOI: 10.1016/j.jmb.2007.11.012. View

Krissinel E, Henrick K . Inference of macromolecular assemblies from crystalline state. J Mol Biol. 2007; 372(3):774-97. DOI: 10.1016/j.jmb.2007.05.022. View

Baker N, Sept D, Joseph S, Holst M, McCammon J . Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A. 2001; 98(18):10037-41. PMC: 56910. DOI: 10.1073/pnas.181342398. View

10.

Emsley P, Cowtan K . Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2126-32. DOI: 10.1107/S0907444904019158. View

11.

Siemann S, Brewer D, Clarke A, Dmitrienko G, Lajoie G, Viswanatha T . IMP-1 metallo-beta-lactamase: effect of chelators and assessment of metal requirement by electrospray mass spectrometry. Biochim Biophys Acta. 2002; 1571(3):190-200. DOI: 10.1016/s0304-4165(02)00258-1. View

12.

Afonine P, Grosse-Kunstleve R, Chen V, Headd J, Moriarty N, Richardson J . phenix.model_vs_data: a high-level tool for the calculation of crystallographic model and data statistics. J Appl Crystallogr. 2010; 43(Pt 4):669-676. PMC: 2906258. DOI: 10.1107/S0021889810015608. View

13.

Concha N, Rasmussen B, Bush K, Herzberg O . Crystal structure of the wide-spectrum binuclear zinc beta-lactamase from Bacteroides fragilis. Structure. 1996; 4(7):823-36. DOI: 10.1016/s0969-2126(96)00089-5. View

14.

Masuda K, Matsuyama S, Tokuda H . Elucidation of the function of lipoprotein-sorting signals that determine membrane localization. Proc Natl Acad Sci U S A. 2002; 99(11):7390-5. PMC: 124241. DOI: 10.1073/pnas.112085599. View

15.

Livermore D . The zeitgeist of resistance. J Antimicrob Chemother. 2007; 60 Suppl 1:i59-61. DOI: 10.1093/jac/dkm160. View

16.

Gonzalez J, Medrano Martin F, Costello A, Tierney D, Vila A . The Zn2 position in metallo-beta-lactamases is critical for activity: a study on chimeric metal sites on a conserved protein scaffold. J Mol Biol. 2007; 373(5):1141-56. DOI: 10.1016/j.jmb.2007.08.031. View

17.

Zhang H, Hao Q . Crystal structure of NDM-1 reveals a common β-lactam hydrolysis mechanism. FASEB J. 2011; 25(8):2574-82. DOI: 10.1096/fj.11-184036. View

18.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

19.

Wang Z, Fast W, Valentine A, Benkovic S . Metallo-beta-lactamase: structure and mechanism. Curr Opin Chem Biol. 1999; 3(5):614-22. DOI: 10.1016/s1367-5931(99)00017-4. View

20.

Winn M, Isupov M, Murshudov G . Use of TLS parameters to model anisotropic displacements in macromolecular refinement. Acta Crystallogr D Biol Crystallogr. 2001; 57(Pt 1):122-33. DOI: 10.1107/s0907444900014736. View