{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:50:48Z","timestamp":1790707848657,"version":"4.1.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2015,6,1]],"date-time":"2015-06-01T00:00:00Z","timestamp":1433116800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"DOI":"10.1371\/journal.ppat.1004949","type":"journal-article","created":{"date-parts":[[2015,6,2]],"date-time":"2015-06-02T01:00:10Z","timestamp":1433206810000},"page":"e1004949","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":115,"title":["Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability"],"prefix":"10.1371","volume":"11","author":[{"given":"Shrenik C.","family":"Mehta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacie","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Palzkill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2015,6,1]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.tim.2006.07.008","article-title":"The \u03b2-lactamase threat in Enterobacteriaceae, <italic>Pseudomonas<\/italic> and <italic>Acinetobacter<\/italic>","volume":"14","author":"DM Livermore","year":"2006","journal-title":"Trends Microbiol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMp0804651","article-title":"Antibiotic-Resistant Bugs in the 21st Century\u2014A Clinical Super-Challenge","volume":"360","author":"CA Arias","year":"2009","journal-title":"N Engl J Med"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0463.2009.02563.x","article-title":"Beta-lactam antibiotics: from antibiosis to resistance and bacteriology","volume":"118","author":"KF Kong","year":"2010","journal-title":"APMIS"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"4943","DOI":"10.1128\/AAC.00296-11","article-title":"Carbapenems: Past, Present, and Future","volume":"55","author":"KM Papp-Wallace","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0002-9343(85)90097-X","article-title":"Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem\/cilastatin","volume":"78","author":"J Birnbaum","year":"1985","journal-title":"Am J Med"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"9748","DOI":"10.1021\/ja9818001","article-title":"Structural Basis for Clinical Longevity of Carbapenem Antibiotics in the Face of Challenge by the Common Class A \u03b2-Lactamases from the Antibiotic-Resistant Bacteria","volume":"120","author":"L Maveyraud","year":"1998","journal-title":"J Am Chem Soc"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"12656","DOI":"10.1021\/ja7111146","article-title":"Inhibition of class A \u03b2-lactamases by carbapenems: crystallographic observation of two conformations of meropenem in SHV-1","volume":"130","author":"M Nukaga","year":"2008","journal-title":"J Am Chem Soc"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"18275","DOI":"10.1021\/ja304460j","article-title":"The basis for carbapenem hydrolysis by class A \u03b2-lactamases: a combined investigation using crystallography and simulations","volume":"134","author":"F Fonseca","year":"2012","journal-title":"J Am Chem Soc"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2174\/1568005033342181","article-title":"\u03b2-lactamases: a survey of protein diversity","volume":"3","author":"MS Helfand","year":"2003","journal-title":"Curr Drug Targets Infect Disord"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1021\/ar0400241","article-title":"Metallo-\u03b2-lactamases: novel weaponry for antibiotic resistance in bacteria","volume":"39","author":"MW Crowder","year":"2006","journal-title":"Acc Chem Res"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ijmm.2010.04.005","article-title":"Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens","volume":"300","author":"Y Pfeifer","year":"2010","journal-title":"Int J Med Microbiol"},{"issue":"Suppl 3","key":"ref12","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/S0924-8579(10)70004-2","article-title":"Emerging carbapenemases: a global perspective","volume":"36","author":"TR Walsh","year":"2010","journal-title":"Int J Antimicrob Agents"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1146\/annurev-micro-090110-102911","article-title":"Epidemiological expansion, structural studies, and clinical challenges of new \u03b2-lactamases from gram-negative bacteria","volume":"65","author":"K Bush","year":"2011","journal-title":"Annu Rev Microbiol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S1473-3099(09)70054-4","article-title":"The real threat of <italic>Klebsiella pneumoniae<\/italic> carbapenemase-producing bacteria","volume":"9","author":"P Nordmann","year":"2009","journal-title":"Lancet Infect Dis"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1128\/AAC.01451-07","article-title":"Genetic structures at the origin of acquisition of the \u03b2-lactamase <italic>bla<\/italic><sub>KPC<\/sub> gene","volume":"52","author":"T Naas","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1128\/AAC.45.4.1151-1161.2001","article-title":"Novel carbapenem-hydrolyzing \u03b2-lactamase, KPC-1, from a carbapenem-resistant strain of <italic>Klebsiella pneumoniae<\/italic>","volume":"45","author":"H Yigit","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"6057","DOI":"10.1128\/AAC.01156-12","article-title":"KPC-9, a novel carbapenemase from clinical specimens in Israel","volume":"56","author":"C Hidalgo-Grass","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"6006","DOI":"10.1128\/AAC.01338-12","article-title":"Antibiotic resistance and substrate profiles of the class A carbapenemase KPC-6","volume":"56","author":"TL Lamoureaux","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1128\/JCM.06115-11","article-title":"Using nucleic acid microarrays to perform molecular epidemiology and detect novel \u03b2-lactamases: a snapshot of extended-spectrum \u03b2-lactamases throughout the world","volume":"50","author":"C Lascols","year":"2012","journal-title":"J Clin Microbiol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1128\/AAC.00899-09","article-title":"Detection of KPC in <italic>Acinetobacter<\/italic> spp. in Puerto Rico","volume":"54","author":"IE Robledo","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1128\/AAC.00734-08","article-title":"Phenotypic and enzymatic comparative analysis of the novel KPC variant KPC-5 and its evolutionary variants, KPC-2 and KPC-4","volume":"53","author":"DJ Wolter","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"4793","DOI":"10.1128\/AAC.48.12.4793-4799.2004","article-title":"Outbreak of <italic>Klebsiella pneumoniae<\/italic> producing a new carbapenem-hydrolyzing class A \u03b2-lactamase, KPC-3, in a New York Medical Center","volume":"48","author":"N Woodford","year":"2004","journal-title":"Antimicrob Agents Chemother"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1021\/bi501195g","article-title":"Molecular Basis for the Catalytic Specificity of the CTX-M Extended-Spectrum \u03b2-Lactamases","volume":"54","author":"CJ Adamski","year":"2014","journal-title":"Biochemistry"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"8509","DOI":"10.1021\/bi00489a001","article-title":"Additivity of mutational effects in proteins","volume":"29","author":"JA Wells","year":"1990","journal-title":"Biochemistry"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/S0969-2126(94)00096-4","article-title":"Stability and function: two constraints in the evolution of barstar and other proteins","volume":"2","author":"G Schreiber","year":"1994","journal-title":"Structure"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1073\/pnas.92.2.452","article-title":"A relationship between protein stability and protein function","volume":"92","author":"BK Shoichet","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0022-2836(02)00400-X","article-title":"Evolution of an Antibiotic Resistance Enzyme Constrained by Stability and Activity Trade-offs","volume":"320","author":"X Wang","year":"2002","journal-title":"J Mol Biol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.jmb.2010.10.008","article-title":"Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM \u03b2-lactamases","volume":"404","author":"NG Brown","year":"2010","journal-title":"J Mol Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"5732","DOI":"10.1021\/bi700300u","article-title":"Crystal structure of KPC-2: insights into carbapenemase activity in class A \u03b2-lactamases","volume":"46","author":"W Ke","year":"2007","journal-title":"Biochemistry"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1021\/bi00227a004","article-title":"Substitution of lysine at position 104 or 240 of TEM-1pTZ18R beta-lactamase enhances the effect of serine-164 substitution on hydrolysis or affinity for cephalosporins and the monobactam aztreonam","volume":"30","author":"JA Sowek","year":"1991","journal-title":"Biochemistry"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"29144","DOI":"10.1074\/jbc.272.46.29144","article-title":"Cephalosporin substrate specificity determinants of TEM-1 \u03b2-lactamase","volume":"272","author":"C Cantu 3rd","year":"1997","journal-title":"J Biol Chem"},{"issue":"Pt 1","key":"ref33","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1042\/bj3050033","article-title":"Multiple substitutions at position 104 of \u03b2-lactamase TEM-1: assessing the role of this residue in substrate specificity","volume":"305","author":"A Petit","year":"1995","journal-title":"Biochem J"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/jac\/dkg256","article-title":"Effect of D240G substitution in a novel ESBL CTX-M-27","volume":"52","author":"R Bonnet","year":"2003","journal-title":"J Antimicrob Chemother"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.jmb.2010.10.008","article-title":"Multiple Global Suppressors of Protein Stability Defects Facilitate the Evolution of Extended-Spectrum TEM \u03b2-Lactamases","volume":"404","author":"NG Brown","year":"2010","journal-title":"J Mol Biol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0022-2836(92)90387-Y","article-title":"Effect of active site residues in barnase on activity and stability","volume":"225","author":"EM Meiering","year":"1992","journal-title":"J Mol Biol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.jmb.2005.02.010","article-title":"Atomic resolution structures of CTX-M \u03b2-lactamases: extended spectrum activities from increased mobility and decreased stability","volume":"348","author":"Y Chen","year":"2005","journal-title":"J Mol Biol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.1073\/pnas.94.16.8801","article-title":"A natural polymorphism in \u03b2-lactamase is a global suppressor","volume":"94","author":"W Huang","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Suppl 1","key":"ref39","doi-asserted-by":"crossref","first-page":"9995","DOI":"10.1073\/pnas.0901522106","article-title":"In the light of directed evolution: pathways of adaptive protein evolution","volume":"106","author":"JD Bloom","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1073\/pnas.0406744102","article-title":"Thermodynamic prediction of protein neutrality","volume":"102","author":"JD Bloom","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/prot.21227","article-title":"Relative tolerance of mesostable and thermostable protein homologs to extensive mutation","volume":"66","author":"W Besenmatter","year":"2007","journal-title":"Proteins"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1073\/pnas.0510098103","article-title":"Protein stability promotes evolvability","volume":"103","author":"JD Bloom","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"e111491","DOI":"10.1371\/journal.pone.0111491","article-title":"Phenotypic and enzymatic comparative analysis of the KPC variants, KPC-2 and its recently discovered variant KPC-15","volume":"9","author":"D Wang","year":"2014","journal-title":"PLoS One"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/208239a0","article-title":"Penicillinase synthesis controlled by infectious R factors in Enterobacteriaceae","volume":"208","author":"N Datta","year":"1965","journal-title":"Nature"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0378-1119(83)90222-6","article-title":"Vectors bearing a hybrid <italic>trp-lac<\/italic> promoter useful for regulated expression of cloned genes in <italic>Escherichia coli<\/italic>","volume":"25","author":"E Amann","year":"1983","journal-title":"Gene"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1074\/jbc.274.4.2394","article-title":"Contributions of aspartate 49 and phenylalanine 142 residues of a tight binding inhibitory protein of \u03b2-lactamases","volume":"274","author":"J Petrosino","year":"1999","journal-title":"J Biol Chem"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1128\/AAC.00215-13","article-title":"BLIP-II is a highly potent inhibitor of <italic>Klebsiella pneumoniae<\/italic> carbapenemase (KPC-2)","volume":"57","author":"NG Brown","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"W597","DOI":"10.1093\/nar\/gks400","article-title":"ExPASy: SIB bioinformatics resource portal","volume":"40","author":"P Artimo","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0959-440X(02)00344-5","article-title":"Rotamer libraries in the 21st century","volume":"12","author":"RL Dunbrack Jr","year":"2002","journal-title":"Curr Opin Struct Biol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"10382","DOI":"10.1074\/jbc.M114.633438","article-title":"A Triple Mutant in the \u03a9-loop of TEM-1 \u03b2-Lactamase Changes the Substrate Profile via a Large Conformational Change and an Altered General Base for Catalysis","volume":"290","author":"V Stojanoski","year":"2015","journal-title":"J Biol Chem"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.ppat.1004949","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,9]],"date-time":"2024-06-09T09:01:57Z","timestamp":1717923717000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1004949"}},"subtitle":[],"editor":[{"given":"Robert","family":"Bonomo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,6,1]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,6,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1004949","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,1]]}}}