Gene Network Analysis of Metallo Beta Lactamase Family Proteins Indicates the Role of Gene Partners in Antibiotic Resistance and Reveals Important Drug Targets

Metallo Beta (β) Lactamases (MBL) are metal dependent bacterial enzymes that hydrolyze the β‐lactam antibiotics. In recent years, MBL have received considerable attention because it inactivates most of the β‐lactam antibiotics. Increase in dissemination of MBL encoding antibiotic resistance genes in pathogenic bacteria often results in unsuccessful treatments. Gene interaction network of MBL provides a complete understanding on the molecular basis of MBL mediated antibiotic resistance. In our present study, we have constructed the MBL network of 37 proteins with 751 functional partners from pathogenic bacterial spp. We found 12 highly interconnecting clusters. Among the 37 MBL proteins considered in the present study, 22 MBL proteins are from B3 subclass, 14 are from B1 subclass and only one is from B2 subclass. Global topological parameters are used to calculate and compare the probability of interactions in MBL proteins. Our results indicate that the proteins associated within the network have a strong influence in antibiotic resistance mechanism. Interestingly, several drug targets are identified from the constructed network. We believe that our results would be helpful for researchers exploring MBL‐mediated antibiotic resistant mechanisms. J. Cell. Biochem. 117: 1330–1339, 2016. © 2015 Wiley Periodicals, Inc.

[1]  D. Court,et al.  Essentiality of Ribosomal and Transcription Antitermination Proteins Analyzed by Systematic Gene Replacement in Escherichia coli , 2007, Journal of bacteriology.

[2]  Andrew V. Sutherland,et al.  Bacterial diaminopimelate metabolism as a target for antibiotic design. , 2000, Bioorganic & medicinal chemistry.

[3]  M. Rohmer,et al.  Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs. , 2004, Current opinion in investigational drugs.

[4]  V. Godoy,et al.  Antibiotic Resistance Acquired through a DNA Damage-Inducible Response in Acinetobacter baumannii , 2013, Journal of bacteriology.

[5]  K. P. Lennox,et al.  Computational analysis of pathogen-borne metallo β-lactamases reveals discriminating structural features between B1 types , 2012, BMC Research Notes.

[6]  Damian Szklarczyk,et al.  The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored , 2010, Nucleic Acids Res..

[7]  J. Frère,et al.  Mutational Analysis of VIM-2 Reveals an Essential Determinant for Metallo-β-Lactamase Stability and Folding , 2010, Antimicrobial Agents and Chemotherapy.

[8]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[9]  P. Nordmann,et al.  Metallo-beta-lactamases: the quiet before the storm? , 2005, Clinical microbiology reviews.

[10]  K. Asai,et al.  A Bacitracin-Resistant Bacillus subtilis Gene Encodes a Homologue of the Membrane-Spanning Subunit of the Bacillus licheniformis ABC Transporter , 2003, Journal of bacteriology.

[11]  Carine Bebrone,et al.  Update of the Standard Numbering Scheme for Class B β-Lactamases , 2004, Antimicrobial Agents and Chemotherapy.

[12]  R. Utsumi,et al.  Novel antibacterial compounds specifically targeting the essential WalR response regulator , 2010, Journal of antibiotics (Tokyo. 1968).

[13]  R. Hakenbeck,et al.  The fib locus in Streptococcus pneumoniae is required for peptidoglycan crosslinking and PBP-mediated beta-lactam resistance. , 2000, FEMS microbiology letters.

[14]  V. Nizet,et al.  Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics , 2012, Antimicrobial Agents and Chemotherapy.

[15]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[16]  J. Davies,et al.  Origins and Evolution of Antibiotic Resistance , 1996, Microbiology and Molecular Biology Reviews.

[17]  Ben Tagger,et al.  Federated ontology-based queries over cancer data , 2012, BMC Bioinformatics.

[18]  B. Weisblum Erythromycin resistance by ribosome modification , 1995, Antimicrobial agents and chemotherapy.

[19]  D. Qu,et al.  Efficacy of novel antibacterial compounds targeting histidine kinase YycG protein , 2014, Applied Microbiology and Biotechnology.

[20]  C. Bebrone Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. , 2007, Biochemical pharmacology.

[21]  Hiromi Daiyasu,et al.  Expansion of the zinc metallo‐hydrolase family of the β‐lactamase fold , 2001 .

[22]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[23]  Natasa Przulj,et al.  Biological network comparison using graphlet degree distribution , 2007, Bioinform..

[24]  D. M. Goodenough-Lashua,et al.  tRNA-guanine transglycosylase from E. coli: a ping-pong kinetic mechanism is consistent with nucleophilic catalysis. , 2003, Bioorganic chemistry.

[25]  Xiaowen Chen,et al.  Topological properties of the drug targets regulated by microRNA in human protein–protein interaction network , 2011, Journal of drug targeting.

[26]  J. Frère,et al.  Standard numbering scheme for class B beta-lactamases. , 2001, Antimicrobial agents and chemotherapy.

[27]  Maria J. Gomez,et al.  Genes Involved in Intrinsic Antibiotic Resistance of Acinetobacter baylyi , 2006, Antimicrobial Agents and Chemotherapy.

[28]  M. Kale,et al.  Exploration of Lysine Pathway for Developing Newer Anti-Microbial Analogs through Enzyme Inhibition Approach , 2014 .

[29]  R. Kohli,et al.  Targets for Combating the Evolution of Acquired Antibiotic Resistance , 2015, Biochemistry.

[30]  Fidel Ramírez,et al.  Computing topological parameters of biological networks , 2008, Bioinform..

[31]  M. Sugai,et al.  Characterization of fmtA, a Gene That Modulates the Expression of Methicillin Resistance in Staphylococcus aureus , 1999, Antimicrobial Agents and Chemotherapy.

[32]  H. Yoneyama,et al.  Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development , 2006, Bioscience, biotechnology, and biochemistry.

[33]  Cathy H. Wu,et al.  UniProt: the Universal Protein knowledgebase , 2004, Nucleic Acids Res..

[34]  Sang Yup Lee,et al.  Rapid one‐step inactivation of single or multiple genes in Escherichia coli , 2013, Biotechnology journal.

[35]  O. Sahin,et al.  Key Role of Mfd in the Development of Fluoroquinolone Resistance in Campylobacter jejuni , 2008, PLoS pathogens.

[36]  D. Žgur-Bertok,et al.  DNA Damage Repair and Bacterial Pathogens , 2013, PLoS pathogens.

[37]  Timothy R. Walsh,et al.  Metallo-β-Lactamases: the Quiet before the Storm? , 2005, Clinical Microbiology Reviews.

[38]  A. Vila,et al.  Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution , 2014, Antibiotics.

[39]  William Sinko,et al.  Antibacterial drug leads targeting isoprenoid biosynthesis , 2012, Proceedings of the National Academy of Sciences.

[40]  J. Barbé,et al.  Acinetobacter baumannii RecA Protein in Repair of DNA Damage, Antimicrobial Resistance, General Stress Response, and Virulence , 2011, Journal of bacteriology.

[41]  Giovanni Scardoni,et al.  Node Interference and Robustness: Performing Virtual Knock-Out Experiments on Biological Networks: The Case of Leukocyte Integrin Activation Network , 2014, PloS one.

[42]  J. Pleiss,et al.  Systematic Analysis of Metallo-β-Lactamases Using an Automated Database , 2012, Antimicrobial Agents and Chemotherapy.

[43]  H Toh,et al.  Expansion of the zinc metallo-hydrolase family of the beta-lactamase fold. , 2001, FEBS letters.

[44]  C. Hutton,et al.  Inhibitors of lysine biosynthesis as antibacterial agents. , 2003, Mini reviews in medicinal chemistry.

[45]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[46]  T. Palzkill Metallo‐β‐lactamase structure and function , 2013, Annals of the New York Academy of Sciences.

[47]  D. Lipman,et al.  Extracting protein alignment models from the sequence database. , 1997, Nucleic acids research.

[48]  J. Goldsmith,et al.  Ampicillin Resistance Is Increased in Escherichia coli K 12 relA and spoT Mutants but Sub-inhibitory Pretreatment Does Not Induce Adaptive Resistance , 2013 .

[49]  Damian Szklarczyk,et al.  STRING v9.1: protein-protein interaction networks, with increased coverage and integration , 2012, Nucleic Acids Res..

[50]  T. Pitt,et al.  Mutators among CTX-M beta-lactamase-producing Escherichia coli and risk for the emergence of fosfomycin resistance. , 2006, The Journal of antimicrobial chemotherapy.

[51]  K. Becker,et al.  The mecA Homolog mecC Confers Resistance against β-Lactams in Staphylococcus aureus Irrespective of the Genetic Strain Background , 2014, Antimicrobial Agents and Chemotherapy.

[52]  L. Engstrand,et al.  Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  D. Green The bacterial cell wall as a source of antibacterial targets , 2002, Expert opinion on therapeutic targets.