{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:34:17Z","timestamp":1790462057068,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T00:00:00Z","timestamp":1462838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Antibiotic resistance is one of the most serious public health problems. Among bacterial resistance, \u03b2-lactam antibiotic resistance is the most prevailing and threatening area. Antibiotic resistance is thought to originate in antibiotic-producing bacteria such as Streptomyces. In this review, \u03b2-lactamases and penicillin-binding proteins (PBPs) in Streptomyces are explored mainly by phylogenetic analyses from the viewpoint of self-resistance. Although PBPs are more important than \u03b2-lactamases in self-resistance, phylogenetically diverse \u03b2-lactamases exist in Streptomyces. While class A \u03b2-lactamases are mostly detected in their enzyme activity, over two to five times more classes B and C \u03b2-lactamase genes are identified at the whole genomic level. These genes can subsequently be transferred to pathogenic bacteria. As for PBPs, two pairs of low affinity PBPs protect Streptomyces from the attack of self-producing and other environmental \u03b2-lactam antibiotics. PBPs with PASTA domains are detectable only in class A PBPs in Actinobacteria with the exception of Streptomyces. None of the Streptomyces has PBPs with PASTA domains. However, one of class B PBPs without PASTA domain and a serine\/threonine protein kinase with four PASTA domains are located in adjacent positions in most Streptomyces. These class B type PBPs are involved in the spore wall synthesizing complex and probably in self-resistance. Lastly, this paper emphasizes that the resistance mechanisms in Streptomyces are very hard to deal with, despite great efforts in finding new antibiotics.<\/jats:p>","DOI":"10.3390\/molecules21050605","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T08:52:17Z","timestamp":1462870337000},"page":"605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Self-resistance in Streptomyces, with Special Reference to \u03b2-Lactam Antibiotics"],"prefix":"10.3390","volume":"21","author":[{"given":"Hiroshi","family":"Ogawara","sequence":"first","affiliation":[{"name":"HO Bio Institute, 33-9, Yushima-2, Bunkyo-ku, Tokyo 113-0034, Japan"},{"name":"Department of Biochemistry, Meiji Pharmaceutical University, 522-1, Noshio-2, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,5,10]]},"reference":[{"key":"ref_1","first-page":"226","article-title":"On the antibacterial action of cultures of penicillium, with special reference to their use in the isolation of B. influenzae","volume":"10","author":"Fleming","year":"1929","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/S0140-6736(01)08728-1","article-title":"Penicillin as a chemotherapeutic agent","volume":"236","author":"Chain","year":"1940","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0140-6736(00)72122-2","article-title":"Further observations in penicillin","volume":"238","author":"Abraham","year":"1941","journal-title":"Lancet"},{"key":"ref_4","first-page":"677","article-title":"An enzyme from bacteria able to destroy penicillin","volume":"10","author":"Abraham","year":"1940","journal-title":"Rev. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/ajcp\/15.10.446","article-title":"Penicillin resistance of Staphylococcus aureus and its clinical implications","volume":"15","author":"Plough","year":"1945","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3181\/00379727-60-15089","article-title":"Penicillin resistant staphylococci","volume":"60","author":"Bondi","year":"1945","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1699-0463.1945.tb04075.x","article-title":"Studies on induced resistance to penicillin in pneumococcus type I","volume":"22","author":"Eriksen","year":"1945","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3181\/00379727-60-15128","article-title":"Production of extracellular penicillin-inactivating substances associated with penicillin resistance in Staphylococcus aureus","volume":"60","author":"Gots","year":"1945","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3181\/00379727-60-15187P","article-title":"Studies on the action of penicillin; development of penicillin resistance by gonococcus","volume":"60","author":"Miller","year":"1945","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"356","DOI":"10.3181\/00379727-60-15188P","article-title":"Studies on action of penicillin; virulence of penicillin resistant strains of meningococcus","volume":"60","author":"Miller","year":"1945","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1084\/jem.83.1.65","article-title":"Studies on the nature of resistance of Gram-negative bacilli to penicillin","volume":"83","author":"Shwartzman","year":"1946","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1073\/pnas.31.6.157","article-title":"Strain specificity and production of antibiotic substances. V. Strain resistance of bacteria to antibiotic substances, especially streptomycin","volume":"31","author":"Waksman","year":"1945","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1128\/AAC.13.5.865","article-title":"Production and property of beta-lactamases in Streptomyces: Comparison of the strains isolated newly and thirty years ago","volume":"13","author":"Ogawara","year":"1978","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10388","article-title":"Antibiotic resistance is ancient","volume":"477","author":"King","year":"2011","journal-title":"Nature"},{"key":"ref_15","unstructured":"About antimicrobial resistance, Available online: http:\/\/www.cdc.gov\/drugresistance\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D443","DOI":"10.1093\/nar\/gkn656","article-title":"ARDB\u2014Antibiotic resistance genes database","volume":"37","author":"Liu","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6683","DOI":"10.1016\/S0021-9258(18)62588-8","article-title":"Streptomycin biosynthesis and metabolism. Enzymatic phosphorylation of dihydrostreptobiosamine moieties of dihydrostreptomycin-(streptidino) phosphate and dihydrostreptomycin by Streptomyces extracts","volume":"245","author":"Walker","year":"1970","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1073\/pnas.70.8.2276","article-title":"Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria","volume":"70","author":"Benveniste","year":"1973","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1128\/mr.45.4.591-619.1981","article-title":"Antibiotic resistance in pathogenic and producing bacteria, with special reference to \u03b2-lactam antibiotics","volume":"45","author":"Ogawara","year":"1981","journal-title":"Microbiol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1126\/science.1155157","article-title":"Bacteria subsisting on antibiotics","volume":"320","author":"Dantas","year":"2008","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1111\/j.1462-2920.2004.00664.x","article-title":"Uncultured soil bacteria are a reservoir of new antibiotic resistance genes","volume":"6","author":"Riesenfeld","year":"2004","journal-title":"Environ. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrmicro1614","article-title":"The antibiotic resistome: The nexus of chemical and genetic diversity","volume":"5","author":"Wright","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1126\/science.1120800","article-title":"Sampling the antibiotic resistome","volume":"311","author":"McGrann","year":"2006","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1126\/science.1220761","article-title":"The shared antibiotic resistome of soil bacteria and human pathogens","volume":"337","author":"Forsberg","year":"2012","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/499398a","article-title":"MRSA: Farming up trouble","volume":"499","author":"Mole","year":"2013","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1126\/science.1159483","article-title":"Antibiotics and antibiotic resistance genes in natural environments","volume":"321","author":"Martinez","year":"2008","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Aminov, R.I. (2011). Horizontal gene exchange in environmental microbiota. Front. Microl., 2.","DOI":"10.3389\/fmicb.2011.00158"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Perry, J.A., and Wright, G.D. (2013). The antibiotic resistance \u201cmobilome\u201d: Searching for the link between environment and clinic. Front. Microbiol., 4.","DOI":"10.3389\/fmicb.2013.00138"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Francino, M.P. (2016). Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistance. Front. Micribiol., 6.","DOI":"10.3389\/fmicb.2015.01543"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1128\/MMBR.05011-11","article-title":"Phylogenetic framework and molecular signatures for the main clades of the phylum Actinobacteria","volume":"76","author":"Gao","year":"2012","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1128\/MMBR.00005-07","article-title":"Genomics of Actinobacteria: Tracing the evolutionary history of an ancient phylum","volume":"71","author":"Ventura","year":"2007","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1574-6976.2009.00206.x","article-title":"The complex extracellular biology of Streptomyces","volume":"34","author":"Chater","year":"2010","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_33","first-page":"9","article-title":"Gene clusters for \u03b2-lactam antibiotics and control of their expression: Why have clusters evolved, and from where did they originate?","volume":"9","author":"Liras","year":"2006","journal-title":"Int. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1128\/MMBR.00054-12","article-title":"Molecular regulation of antibiotic biosynthesis in streptomyces","volume":"77","author":"Liu","year":"2013","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7164\/antibiotics.32.1","article-title":"Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties","volume":"32","author":"Kahan","year":"1979","journal-title":"J. Antibiot."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1128\/AAC.11.5.852","article-title":"Clavulanic acid: A beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus","volume":"11","author":"Reading","year":"1977","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1080\/10408410091154228","article-title":"Penicillin binding proteins, \u03b2-lactams, and lactamases: Offensives, attacks, and defensive countermeasures","volume":"26","author":"Koch","year":"2000","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1073\/pnas.38.9.775","article-title":"Analysis of the biochemical mechanism of drug resistance in certain bacterial mutants","volume":"38","author":"Davis","year":"1952","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","unstructured":"The Comprehensive Antibiotic Resistance Database. Available online: http:\/\/arpcard.mcmaster.ca\/."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"King, D.T., Sobhanifar, S., and Strynadka, N.C. (2016). One ring to rule them all: Current trends in combating bacterial resistance to the \u03b2-lactams. Protein Sci.","DOI":"10.1002\/pro.2889"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s10295-010-0721-x","article-title":"Avoidance of suicide in antibiotic-producing microbes","volume":"37","author":"Cundliffe","year":"2010","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.1128\/AAC.00419-13","article-title":"The comprehensive antibiotic resistance database","volume":"57","author":"McArthur","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/ismej.2014.106","article-title":"Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology","volume":"9","author":"Gibson","year":"2015","journal-title":"ISME J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0065-2911(08)60376-8","article-title":"The \u03b2-lactamases of gram-negative bacteria and their possible physiological role","volume":"9","author":"Richmond","year":"1973","journal-title":"Adv. Microb. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1128\/AAC.8.4.402","article-title":"Production and property of \u03b2-lactamases in Streptomyces","volume":"8","author":"Ogawara","year":"1975","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","unstructured":"Hamilton-Miller, J.M.T., and Smith, J.T. (1979). Beta-Lactamases, Academic Press."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/BF00429338","article-title":"Penicillinase (\u03b2-lactamase) formation by blue-green algae","volume":"112","author":"Kushner","year":"1977","journal-title":"Arch. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"32516","DOI":"10.1074\/jbc.M805375200","article-title":"A new family of cyanobacterial penicillin-binding proteins. A missing link in the evolution of class A \u03b2-lactamases","volume":"283","author":"Urbach","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17216","DOI":"10.1074\/jbc.M808392200","article-title":"Structure of PhnP, a phosphodiesterase of the carbon-phosphorus lyase pathway for phosphonate degradation","volume":"284","author":"Podzelinska","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"18914","DOI":"10.1074\/jbc.M115.652537","article-title":"Characterizations of two bacterial persulfide dioxygenases of the metallo-\u03b2-lactamase superfamily","volume":"290","author":"Sattler","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(01)02686-2","article-title":"Expansion of the zinc metallo-hydrolase family of the \u03b2-lactamase fold","volume":"503","author":"Daiyasu","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/10409230701279118","article-title":"Nucleases of the metallo-\u03b2-lactamase family and their role in DNA and RNA metabolism","volume":"42","author":"Dominski","year":"2007","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1515\/BC.2005.142","article-title":"The tRNase Z family of proteins: Physiological functions, substrate specificity and structural properties","volume":"386","author":"Vogel","year":"2005","journal-title":"Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1128\/JB.00404-11","article-title":"Genomes of three methylotrophs from a single niche reveal the genetic and metabolic divergence of the Methylophilaceae","volume":"193","author":"Lapidus","year":"2011","journal-title":"J. Bacteriol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8491","DOI":"10.1021\/bi9010539","article-title":"Arabidopsis thaliana mitochondrial glyoxalase 2-1 exhibits \u03b2-lactamase activity","volume":"48","author":"Limphong","year":"2009","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1101\/gr.2889405","article-title":"Gene and alternative splicing annotation with AIR","volume":"15","author":"Florea","year":"2005","journal-title":"Genome Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1006\/geno.2001.6643","article-title":"Identification, genomic organization, and mRNA expression of LACTB, encoding a serine \u03b2-lactamase-like protein with an amino-terminal transmembrane domain","volume":"78","author":"Smith","year":"2001","journal-title":"Genomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1021\/ja908850p","article-title":"An antibiotic-resistance enzyme from a deep-sea bacterium","volume":"132","author":"Toth","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1111\/j.1742-4658.2008.06324.x","article-title":"Crystal structure of a cold-adapted class C \u03b2-lactamase","volume":"275","author":"Michaux","year":"2008","journal-title":"FEBS J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1107\/S1744309109005442","article-title":"Purification, crystallization and preliminary crystallographic analysis of Est-Y29: A novel oligomeric \u03b2-lactamase","volume":"65","author":"Kim","year":"2009","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/ismej.2008.86","article-title":"Functional metagenomics reveals diverse \u03b2-lactamases in a remote Alaskan soil","volume":"3","author":"Allen","year":"2009","journal-title":"ISME J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4396","DOI":"10.1128\/AEM.01763-09","article-title":"Metagenomic analysis of apple orchard soil reveals antibiotic resistance genes encoding predicted bifunctional proteins","volume":"76","author":"Donato","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_63","first-page":"350","article-title":"Characterization of a bifunctional \u03b2-lactamase\/ribonuclease and its interaction with a chaperone-like protein in the pathogen Mycobacterium tuberculosis H37Rv","volume":"76","author":"Sun","year":"2011","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.enzmictec.2015.10.007","article-title":"Characterization of a novel esterase Rv1497 of Mycobacterium tuberculosis H37Rv demonstrating \u03b2-lactamase activity","volume":"82","author":"Singh","year":"2016","journal-title":"Enzyme Microb. Technol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1098\/rstb.1980.0049","article-title":"The structure of beta-lactamases","volume":"289","author":"Ambler","year":"1980","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1128\/AAC.01009-09","article-title":"Updated functional classification of \u03b2-lactamases","volume":"54","author":"Bush","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.1073\/pnas.78.8.4897","article-title":"ampC cephalosporinase of Escherichia coli K-12 has a different evolutionary origin from that of beta-lactamases of the penicillinase type","volume":"78","author":"Jaurin","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"7378","DOI":"10.1073\/pnas.84.21.7378","article-title":"Precise insertion of antibiotic resistance determinants into Tn21-like transposons: Nucleotide sequence of the OXA-1 \u03b2-lactamase gene","volume":"84","author":"Ouellette","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1749-6632.2012.06796.x","article-title":"Metallo-\u03b2-lactamase structure and function","volume":"1277","author":"Palzkill","year":"2013","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1093\/jac\/dki155","article-title":"Is it necessary to change the classification of \u03b2-lactamases?","volume":"55","author":"Galleni","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1128\/AAC.39.6.1211","article-title":"A functional classification scheme for \u03b2-lactamases and its correlation with molecular structure","volume":"39","author":"Bush","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1128\/CMR.14.4.933-951.2001","article-title":"Extended-spectrum \u03b2-lactamases in the 21st century: Characterization, epidemiology, and detection of this important resistance threat","volume":"14","author":"Bradford","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.tibs.2015.12.007","article-title":"The chemical biology of human metallo-\u03b2-lactamase fold proteins","volume":"41","author":"Pettinati","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1016\/j.bcp.2007.05.021","article-title":"Metallo-\u03b2-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily","volume":"74","author":"Bebrone","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1128\/AAC.49.7.2778-2784.2005","article-title":"Structure-based phylogeny of the metallo-\u03b2-lactamases","volume":"49","author":"Garau","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1128\/CMR.18.2.306-325.2005","article-title":"Metallo-\u03b2-lactamases: The quiet before the storm?","volume":"18","author":"Walsh","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/mpev.1993.1010","article-title":"Phylogenetic tree and sequence similarity of \u03b2-lactamases","volume":"2","author":"Ogawara","year":"1993","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_78","first-page":"1","article-title":"Self-resistance to \u03b2-lactam antibiotics in Streptomyces (in Japanese)","volume":"43","author":"Ogawara","year":"2014","journal-title":"Bull. Meiji Pharmaceut. Univ."},{"key":"ref_79","first-page":"1","article-title":"Molecular phylogenetics of \u03b2-lactamases in Actinobacteria","volume":"42","author":"Ogawara","year":"2013","journal-title":"Bull. Meiji Pharmaceut. Univ."},{"key":"ref_80","unstructured":"BioProject, Available online: http:\/\/www.ncbi.nlm.nih.gov\/guide\/all\/."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1099\/00207713-47-2-479","article-title":"Proposal for a New Hierarchic Classification System, Actinobacteria classis nov.","volume":"47","author":"Stackebrandt","year":"1997","journal-title":"Int. J. Syst. Bacteriol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1128\/AAC.43.12.3014","article-title":"Distribution of \u03b2-lactamases in actinomycetes","volume":"43","author":"Ogawara","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: Multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmbi.2000.4042","article-title":"T-Coffee: A novel method for fast and accurate multiple sequence alignment","volume":"302","author":"Notredame","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1128\/AAC.45.3.660-663.2001","article-title":"Metallo-\u03b2-lactamases Working Group. Standard numbering scheme for class B beta-lactamases","volume":"45","author":"Galleni","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"11257","DOI":"10.1073\/pnas.90.23.11257","article-title":"Evolution of an enzyme activity: Crystallographic structure at 2-A resolution of cephalosporinase from the ampC gene of Enterobacter cloacae P99 and comparison with a class A penicillinase","volume":"90","author":"Lobkovsky","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1128\/MMBR.66.4.702-738.2002","article-title":"Biochemistry and comparative genomics of SxxK superfamily acyltransferases offer a clue to the mycobacterial paradox: Presence of penicillin-susceptible target proteins versus lack of efficiency of penicillin as therapeutic agent","volume":"66","author":"Goffin","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/bioinformatics\/btm404","article-title":"Clustal W and Clustal X version 2.0","volume":"23","author":"Larkin","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_89","unstructured":"\u03b2-Lactamase Classification and Amino Acid Sequences for TEM, SHV and OXA Extended-Spectrum and Inhibitor Resistant Enzymes. Available online: http:\/\/www.lahey.org\/studies\/."},{"key":"ref_90","unstructured":"Protdist-Program to Compute Distance Matrix from Protein Sequences. Available online: http:\/\/evolution.genetics.washington.edu\/phylip\/doc\/protdist.html."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7164\/antibiotics.43.1483","article-title":"Cloning from Streptomyces cellulosae of the gene encoding beta-lactamase, a blue-dextran binding protein","volume":"43","author":"Urabe","year":"1990","journal-title":"J. Antibiot."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0378-1119(93)90769-Y","article-title":"Sequence of a gene encoding \u03b2-lactamase from Streptomyces cellulosae","volume":"124","author":"Ogawara","year":"1993","journal-title":"Gene"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1128\/AAC.48.1.192-202.2004","article-title":"Five additional genes are involved in clavulanic acid biosynthesis in Streptomyces clavuligerus","volume":"48","author":"Jensen","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1128\/JB.182.14.4087-4095.2000","article-title":"Expansion of the clavulanic acid gene cluster: Identification and in vivo functional analysis of three new genes required for biosynthesis of clavulanic acid by Streptomyces clavuligerus","volume":"182","author":"Li","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1128\/CMR.00036-08","article-title":"AmpC \u03b2-lactamases","volume":"22","author":"Jacoby","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1574-6976.2006.00024.x","article-title":"Penicillin binding proteins: Key players in bacterial cell cycle and drug resistance processes","volume":"30","author":"Macheboeuf","year":"2006","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nrmicro2677","article-title":"From the regulation of peptidoglycan synthesis to bacterial growth and morphology","volume":"10","author":"Typas","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1128\/MMBR.00016-07","article-title":"Lipid intermediates in the biosynthesis of bacterial peptidoglycan","volume":"71","year":"2007","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5279","DOI":"10.1016\/S0021-9258(20)81102-8","article-title":"Multiple penicillin-binding components in Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, and Escherichia coli","volume":"247","author":"Suginaka","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1073\/pnas.72.8.2999","article-title":"Distinct penicillin binding proteins involved in the division, elongation, and shape of Escherichia coli K12","volume":"72","author":"Spratt","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1007\/s00018-008-7591-7","article-title":"Substrate specificity of bacterial DD-peptidases (penicillin-binding proteins)","volume":"65","author":"Pratt","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.1574-6976.2008.00105.x","article-title":"The penicillin-binding proteins: Structure and role in peptidoglycan biosynthesis","volume":"32","author":"Sauvage","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/ja.2014.148","article-title":"Penicillin-binding proteins in Actinobacteria","volume":"68","author":"Ogawara","year":"2015","journal-title":"J. Antib."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1128\/MMBR.62.4.1079-1093.1998","article-title":"Multimodular penicillin-binding proteins: An enigmatic family of orthologs and paralogs","volume":"62","author":"Goffin","year":"1998","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s10529-005-6071-5","article-title":"Characterization of pbpA and pbp2 encoding penicillin-binding proteins located on the downstream of clavulanic acid gene cluster in Streptomyces clavuligerus","volume":"28","author":"Ishida","year":"2006","journal-title":"Biotechnol. Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.17.1.1","article-title":"Penicillin-binding proteins of Streptomyces cacaoi, Streptomyces olivaceus, and Streptomyces clavuligerus","volume":"17","author":"Ogawara","year":"1980","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6266","DOI":"10.1128\/jb.178.21.6266-6274.1996","article-title":"Molecular analysis of a \u03b2-lactam resistance gene encoded within the cephamycin gene cluster of Streptomyces clavuligerus","volume":"178","author":"Paradkar","year":"1996","journal-title":"J. Bacteriol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"Protein kinases 6. The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification","volume":"9","author":"Hanks","year":"1995","journal-title":"FASEB J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ceb.2009.01.028","article-title":"Tyrosine phosphorylation: Thirty years and counting","volume":"21","author":"Hunter","year":"2009","journal-title":"Curr Opin. Cell Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/0092-8674(91)90372-6","article-title":"A gene encoding a protein serine\/threonine kinase is required for normal development of M. xanthus, a gram-negative bacterium","volume":"67","author":"Inouye","year":"1991","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1128\/MMBR.00042-10","article-title":"Eukaryote-like serine\/threonine kinases and phosphatases in bacteria","volume":"75","author":"Pereira","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/femsre\/fuv041","article-title":"Role of eukaryotic-like serine\/threonine kinases in bacterial cell division and morphogenesis","volume":"40","author":"Manuse","year":"2016","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.tim.2004.12.006","article-title":"One-component systems dominate signal transduction in prokaryotes","volume":"13","author":"Ulrich","year":"2005","journal-title":"Trends. Microbiol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S0968-0004(02)02164-3","article-title":"The PASTA domain: A \u03b2-lactam-binding domain","volume":"27","author":"Yeats","year":"2002","journal-title":"Trends Biochem. Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1006\/jmbi.2000.3740","article-title":"The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: Implication in drug resistance","volume":"299","author":"Gordon","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/bip.22447","article-title":"Structural and binding properties of the PASTA domain of PonA2, a key penicillin binding protein from Mycobacterium tuberculosis","volume":"101","author":"Calvanese","year":"2014","journal-title":"Biopolymers"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"756","DOI":"10.2174\/138920312804871201","article-title":"Bacterial cell division regulation by Ser\/Thr kinases: A structural perspective","volume":"13","author":"Ruggiero","year":"2012","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/mmi.12588","article-title":"Streptococcus pneumoniae PBP2x mid-cell localization requires the C-terminal PASTA domains and is essential for cell shape maintenance","volume":"92","author":"Peters","year":"2014","journal-title":"Mol. Microbiol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Ogawara, H. (2016). Distribution of PASTA domains in penicillin-binding proteins and serine\/threonine kinases of Actinobacteria. J. Antibiot.","DOI":"10.1038\/ja.2015.138"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1574-6976.2011.00317.x","article-title":"Signals and regulators that govern Streptomyces development","volume":"36","author":"McCormick","year":"2012","journal-title":"FEMS Micribiol. Rev."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Ladwig, N., Franz-Wachtel, M., Hezel, F., Soufi, B., Macek, B., Wohlleben, W., and Muth, G. (2015). Control of morphological differentiation of Streptomyces coelicolor A3(2) by phosphorylation of MreC and PBP2. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125425"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1751-7915.2010.00237.x","article-title":"Forkhead-associated proteins genetically linked to the serine\/threonine kinase PknB regulate carbon flux towards antibiotic biosynthesis in Streptomyces coelicolor","volume":"4","author":"Jones","year":"2011","journal-title":"Microb. Biotechnol."},{"key":"ref_123","first-page":"6028","article-title":"The bla gene of the cephamycin cluster of Streptomyces clavuligerus encodes a class A \u03b2-lactamase of low enzymatic activity","volume":"179","author":"Galleni","year":"1997","journal-title":"J. Bacteriol."},{"key":"ref_124","unstructured":"Streptomyces clavuligerus ATCC 27064 chromosome, whole genome shotgun sequence, Available online: http:\/\/www.ncbi.nlm.nih.gov\/nuccore\/294323433?report=graph."},{"key":"ref_125","unstructured":"Streptomyces cattleya NRRL 8057 = DSM 46488, complete genome, Available online: http:\/\/www.ncbi.nlm.nih.gov\/nuccore\/357397620?report=graph."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s10295-012-1191-0","article-title":"Biosynthesis of clavam metabolites","volume":"39","author":"Jensen","year":"2012","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/ja.2013.26","article-title":"Clavulanic acid production by Streptomyces clavuligerus: Biogenesis, regulation and strain improvement","volume":"66","author":"Paradkar","year":"2013","journal-title":"J. Antibiot."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1099\/00221287-148-5-1427","article-title":"The clavulanic acid biosynthetic cluster of Streptomyces clavuligerus: Genetic organization of the region upstream of the car gene","volume":"148","author":"Mellado","year":"2002","journal-title":"Microbiology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/j.1460-2075.1993.tb05696.x","article-title":"Genes for a \u03b2-lactamase, a penicillin-binding protein and a transmembrane protein are clustered with the cephamycin biosynthetic genes in Nocardia lactamdurans","volume":"12","author":"Coque","year":"1993","journal-title":"EMBO J."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/BF00172490","article-title":"Molecular analysis of the gene cluster involved in cephalosporin biosynthesis from Lysobacter lactamgenus YK90","volume":"44","author":"Kimura","year":"1996","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF01569737","article-title":"Clusters of genes for the biosynthesis of antibiotics: Regulatory genes and overproduction of pharmaceuticals","volume":"9","author":"Martin","year":"1992","journal-title":"J. Ind. Microbiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.phytochem.2005.02.030","article-title":"Evolution of \u03b2-lactam biosynthesis genes and recruitment of trans-acting factors","volume":"66","author":"Brakhage","year":"2005","journal-title":"Phytochemistry"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Barka, E.A., Vatsa, P., Sanchez, L., Gaveau-Vaillant, N., Jacquard, C., Klenk, H.P., Cl\u00e9ment, C., Ouhdouch, Y., and van Wezel, G.P. (2016). Taxonomy, Physiology, and Natural Products of Actinobacteria. Microbiol. Mol. Biol. Rev., 80.","DOI":"10.1128\/MMBR.00044-16"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.arcmed.2005.06.009","article-title":"Resistance to antibiotics: Are we in the post-antibiotic era?","volume":"36","author":"Alanis","year":"2005","journal-title":"Arch. Med. Res."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Cooper, M.A., and Shlaes, D. (2014). Fix the antibiotics pipeline. Nature, 472.","DOI":"10.1038\/472032a"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1039\/b617765b","article-title":"Systems biology of antibiotic production by microorganisms","volume":"24","author":"Rokem","year":"2007","journal-title":"Nat. Prod. Rep."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.tim.2007.10.004","article-title":"Marine actinobacteria: New opportunities for natural product search and discovery","volume":"15","author":"Bull","year":"2007","journal-title":"Trends Microbiol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s10295-013-1325-z","article-title":"Importance of microbial natural products and the need to revitalize their discovery","volume":"41","author":"Demain","year":"2014","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s10295-013-1389-9","article-title":"Microbial genome mining for accelerated natural products discovery: Is a renaissance in the making?","volume":"41","author":"Bachmann","year":"2014","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10295-015-1723-5","article-title":"Natural product discovery: Past, present, and future","volume":"43","author":"Katz","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s10295-015-1682-x","article-title":"Genetic manipulation of secondary metabolite biosynthesis for improved production in Streptomyces and other actinomycetes","volume":"43","author":"Baltz","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/5\/605\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:23:36Z","timestamp":1760210616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/5\/605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,10]]},"references-count":141,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,5]]}},"alternative-id":["molecules21050605"],"URL":"https:\/\/doi.org\/10.3390\/molecules21050605","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,10]]}}}