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We here systematically investigate the composition of these enzymes in order to gain insights into their associated biological processes, potential ways to disrupt them via chemotherapeutics, and strategies by which they might be leveraged as recombinant antibacterial biotherapies. To do so, we developed LEDGOs (lytic enzyme domains grouped by organism), a pipeline to create and analyze databases of autolytic enzyme sequences, constituent domain annotations, and architectural patterns of multi-domain enzymes that integrate peptidoglycan binding and degrading functions. We applied LEDGOs to eight pathogenic bacteria, gram negatives <jats:italic>Acinetobacter baumannii<\/jats:italic>, <jats:italic>Klebsiella pneumoniae<\/jats:italic>, <jats:italic>Neisseria gonorrhoeae<\/jats:italic>, and <jats:italic>Pseudomonas aeruginosa<\/jats:italic>; and gram positives <jats:italic>Clostridioides difficile<\/jats:italic>, <jats:italic>Enterococcus faecium<\/jats:italic>, <jats:italic>Staphylococcus aureus<\/jats:italic>, and <jats:italic>Streptococcus pneumoniae<\/jats:italic>. Our analysis of the autolytic enzyme repertoires of these pathogens reveals commonalities and differences in their key domain building blocks and architectures, including correlations and preferred orders among domains in multi-domain enzymes, repetitions of homologous binding domains with potentially complementarity recognition modalities, and sequence similarity patterns indicative of potential divergence of functional specificity among related domains. We have further identified a variety of unannotated sequence regions within the lytic enzymes that may themselves contain new domains with important functions.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008889","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T18:40:56Z","timestamp":1617302456000},"page":"e1008889","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":27,"title":["Building blocks and blueprints for bacterial autolysins"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3208-8871","authenticated-orcid":true,"given":"Spencer J.","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0740-0624","authenticated-orcid":true,"given":"Deeptak","family":"Verma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-3394","authenticated-orcid":true,"given":"Karl E.","family":"Griswold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1860-0912","authenticated-orcid":true,"given":"Chris","family":"Bailey-Kellogg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,1]]},"reference":[{"key":"pcbi.1008889.ref001","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3109\/1040841X.2012.723675","article-title":"Bacteriophage virion-associated peptidoglycan hydrolases: Potential new enzybiotics","author":"L Rodr\u00edguez-Rubio","year":"2013","journal-title":"Critical Reviews in Microbiology"},{"key":"pcbi.1008889.ref002","first-page":"299","volume-title":"Advances in Virus Research","author":"DC Nelson","year":"2012"},{"key":"pcbi.1008889.ref003","first-page":"529","volume-title":"Current Topics in Microbiology and Immunology","author":"VA Fischetti","year":"2017"},{"key":"pcbi.1008889.ref004","first-page":"18","volume-title":"Current Opinion in Microbiology","author":"M Wittekind","year":"2016"},{"key":"pcbi.1008889.ref005","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1021\/cb1001119","article-title":"Enhanced Antimicrobial Activity of Engineered Human Lysozyme","volume":"5","author":"TC Scanlon","year":"2010","journal-title":"ACS Chem Biol"},{"key":"pcbi.1008889.ref006","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1079\/9781845939434.0147","volume-title":"Antimicrobial Drug Discovery: Emerging Strategies","author":"JF Kokai-Kun","year":"2012"},{"key":"pcbi.1008889.ref007","doi-asserted-by":"crossref","first-page":"eabb9011","DOI":"10.1126\/sciadv.abb9011","article-title":"Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing","volume":"6","author":"H Zhao","year":"2020","journal-title":"Sci Adv"},{"key":"pcbi.1008889.ref008","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1172\/JCI136577","article-title":"Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis","volume":"130","author":"VG Fowler","year":"2020","journal-title":"J Clin Invest"},{"key":"pcbi.1008889.ref009","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1128\/AAC.02232-13","article-title":"Preclinical safety evaluation of intravenously administered SAL200 containing the recombinant phage endolysin SAL-1 as a pharmaceutical ingredient","volume":"58","author":"SY Jun","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008889.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00342-19","article-title":"Lysocins: Bioengineered antimicrobials that deliver lysins across the outer membrane of Gram-negative bacteria","volume":"63","author":"RD Heselpoth","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008889.ref011","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1042\/BST20150192","article-title":"From endolysins to Artilysins: Novel enzyme-based approaches to kill drug-resistant bacteria","volume":"44","author":"H Gerstmans","year":"2016","journal-title":"Biochem Soc Trans"},{"key":"pcbi.1008889.ref012","article-title":"Bacteriophage-derived endolysins applied as potent biocontrol agents to enhance food safety","author":"Y. Chang","year":"2020","journal-title":"Microorganisms. 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Wichtig Editore s.r.l."},{"key":"pcbi.1008889.ref028","doi-asserted-by":"crossref","first-page":"6315","DOI":"10.1007\/s00253-015-6443-2","article-title":"Discovery of novel S. aureus autolysins and molecular engineering to enhance bacteriolytic activity","volume":"99","author":"DC Osipovitch","year":"2015","journal-title":"Appl Microbiol Biotechnol"},{"key":"pcbi.1008889.ref029","first-page":"362","article-title":"Fusion with a cell wall binding domain renders autolysin LytM a potent anti-Staphylococcus aureus agent","author":"DC Osipovitch","year":"2015","journal-title":"FEMS Microbiol Lett"},{"key":"pcbi.1008889.ref030","first-page":"151","article-title":"LytU-SH3b fusion protein as a novel and efficient enzybiotic against methicillin-resistant Staphylococcus aureus","volume":"8","author":"M Taheri-Anganeh","year":"2019","journal-title":"Mol Biol Res Commun"},{"key":"pcbi.1008889.ref031","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1021\/acs.biomac.9b01134","article-title":"Modular Assembly of Unique Chimeric Lytic Enzymes on a Protein Scaffold Possessing Anti-Staphylococcal Activity.","volume":"20","author":"D Kim","year":"2019","journal-title":"Biomacromolecules."},{"key":"pcbi.1008889.ref032","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ijfoodmicro.2016.10.030","article-title":"Characterization of three autolysins with activity against cereulide-producing Bacillus isolates in food matrices","volume":"241","author":"P Geng","year":"2017","journal-title":"Int J Food Microbiol"},{"key":"pcbi.1008889.ref033","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1365-2958.1991.tb00752.x","article-title":"A family of clostridial and streptococcal ligand-binding proteins with conserved C-terminal repeat sequences","volume":"5","author":"BW Wren","year":"1991","journal-title":"Mol Microbiol"},{"key":"pcbi.1008889.ref034","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1111\/j.1365-2958.2008.06211.x","article-title":"LysM, a widely distributed protein motif for binding to (peptido)glycans","author":"G Buist","year":"2008","journal-title":"Molecular Microbiology. 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Frontiers Research Foundation"},{"key":"pcbi.1008889.ref042","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1111\/mmi.14349","article-title":"Lytic transglycosylases RlpA and MltC assist in Vibrio cholerae daughter cell separation","volume":"112","author":"AI Weaver","year":"2019","journal-title":"Mol Microbiol"},{"key":"pcbi.1008889.ref043","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1128\/AAC.45.5.1431-1437.2001","article-title":"Mechanism and suppression of lysostaphin resistance in oxacillin-resistant Staphylococcus aureus","volume":"45","author":"MW Climo","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008889.ref044","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1128\/AAC.00786-06","article-title":"Lysostaphin-resistant variants of Staphylococcus aureus demonstrate reduced fitness in vitro and in vivo","volume":"51","author":"C Kusuma","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008889.ref045","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01707-20","article-title":"Deimmunized Lysostaphin Synergizes with Small-molecule Chemotherapies and Re-sensitizes MRSA to \u03b2-Lactam Antibiotics","volume":"65","author":"Y Fang","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008889.ref046","doi-asserted-by":"crossref","unstructured":"CDC. Antibiotic resistance threats in the United States, 2019. 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Bioinformatics"},{"key":"pcbi.1008889.ref057","first-page":"152","volume-title":"Proceedings\u20142004 IEEE Computational Systems Bioinformatics Conference, CSB 2004","author":"R Kuang","year":"2004"},{"key":"pcbi.1008889.ref058","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.1073\/pnas.95.11.5857","article-title":"SMART, a simple modular architecture research tool: Identification of signaling domains","volume":"95","author":"J Schultz","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1008889.ref059","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1093\/bib\/bbx117","article-title":"Microbial genome analysis: The COG approach","volume":"20","author":"MY Galperin","year":"2018","journal-title":"Brief Bioinform"},{"key":"pcbi.1008889.ref060","unstructured":"Protein Clusters\u2014NCBI. Available: https:\/\/www.ncbi.nlm.nih.gov\/proteinclusters"},{"key":"pcbi.1008889.ref061","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/nar\/29.1.41","article-title":"TIGRFAMs: A protein family resource for the functional identification of proteins","volume":"29","author":"DH Haft","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref062","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1186\/s12859-019-3019-7","article-title":"HH-suite3 for fast remote homology detection and deep protein annotation","volume":"20","author":"M Steinegger","year":"2019","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1008889.ref063","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2174\/0929866526666191002104735","article-title":"A Computational Method for the Identification of Endolysins and Autolysins","volume":"27","author":"L Xu","year":"2019","journal-title":"Protein Pept Lett"},{"key":"pcbi.1008889.ref064","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/nprot.2012.085","article-title":"Template-based protein structure modeling using the RaptorX web server","volume":"7","author":"M K\u00e4llberg","year":"2012","journal-title":"Nat Protoc"},{"key":"pcbi.1008889.ref065","doi-asserted-by":"crossref","first-page":"D508","DOI":"10.1093\/nar\/gks1226","article-title":"D2P2: Database of disordered protein predictions","volume":"41","author":"ME Oates","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref066","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1006\/jmbi.2000.4315","article-title":"Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes","volume":"305","author":"A Krogh","year":"2001","journal-title":"J Mol Biol"},{"key":"pcbi.1008889.ref067","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1080\/07391102.2012.743438","article-title":"Understanding the role of domain-domain linkers in the spatial orientation of domains in multi-domain proteins","volume":"31","author":"RM Bhaskara","year":"2013","journal-title":"J Biomol Struct Dyn"},{"key":"pcbi.1008889.ref068","first-page":"325","volume-title":"Protein Engineering, Design and Selection","author":"JS Klein","year":"2014"},{"key":"pcbi.1008889.ref069","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.addr.2012.09.039","article-title":"Fusion protein linkers: Property, design and functionality","author":"X Chen","year":"2013","journal-title":"Advanced Drug Delivery Reviews"},{"key":"pcbi.1008889.ref070","doi-asserted-by":"crossref","first-page":"644","DOI":"10.3389\/fgene.2018.00644","article-title":"PhageWeb\u2013Web Interface for Rapid Identification and Characterization of Prophages in Bacterial Genomes","volume":"9","author":"AL de Sousa","year":"2018","journal-title":"Front Genet"},{"key":"pcbi.1008889.ref071","doi-asserted-by":"crossref","first-page":"W347","DOI":"10.1093\/nar\/gkr485","article-title":"PHAST: A Fast Phage Search Tool","volume":"39","author":"Y Zhou","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref072","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/mmi.12643","article-title":"The bacterial septal ring protein RlpA is a lytic transglycosylase that contributes to rod shape and daughter cell separation in Pseudomonas aeruginosa","volume":"93","author":"MA Jorgenson","year":"2014","journal-title":"Mol Microbiol"},{"key":"pcbi.1008889.ref073","unstructured":"Bayer M. SQLAlchemy. In: Brown A, Wilson G, editors. The Architecture of Open Source Applications Volume II: Structure, Scale, and a Few More Fearless Hacks. 2012."},{"key":"pcbi.1008889.ref074","doi-asserted-by":"crossref","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: A worldwide hub of protein knowledge","volume":"47","author":"A. Bateman","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref075","doi-asserted-by":"crossref","first-page":"D330","DOI":"10.1093\/nar\/gky1055","article-title":"The Gene Ontology Resource: 20 years and still GOing strong","volume":"47","author":"S Carbon","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref076","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology","author":"M Ashburner","year":"2000","journal-title":"Nature Genetics"},{"key":"pcbi.1008889.ref077","first-page":"282","volume-title":"Bioinformatics.","author":"W Li","year":"2001"},{"key":"pcbi.1008889.ref078","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: a new generation of protein database search programs","volume":"25","author":"SF Altschul","year":"1997","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref079","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-10-421","article-title":"BLAST+: Architecture and applications","volume":"10","author":"C Camacho","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1008889.ref080","doi-asserted-by":"crossref","first-page":"D351","DOI":"10.1093\/nar\/gky1100","article-title":"InterPro in 2019: Improving coverage, classification and access to protein sequence annotations","volume":"47","author":"AL Mitchell","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008889.ref081","unstructured":"PyWaffle. Available: https:\/\/github.com\/gyli\/PyWaffle"},{"key":"pcbi.1008889.ref082","first-page":"127","article-title":"Graphviz and dynagraph\u2013static and dynamic graph drawing tools","author":"J Ellson","year":"2003","journal-title":"GRAPH Draw Softw."},{"key":"pcbi.1008889.ref083","unstructured":"Hagber A, Schult D, Renieris M. PyGraphViz."},{"key":"pcbi.1008889.ref084","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v053.i09","article-title":"Fastcluster: Fast hierarchical, agglomerative clustering routines for R and Python","volume":"53","author":"D. M\u00fcllner","year":"2013","journal-title":"J Stat Softw"},{"key":"pcbi.1008889.ref085","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","author":"JD Hunter","year":"2007","journal-title":"Comput Sci Eng"},{"key":"pcbi.1008889.ref086","article-title":"the seaborn development team. mwaskom\/seaborn","author":"M Waskom","year":"2020","journal-title":"Zenodo"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008889","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008889","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T18:50:55Z","timestamp":1618599055000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008889"}},"subtitle":[],"editor":[{"given":"Sergei L.","family":"Kosakovsky Pond","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":86,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008889","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1008889","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,1]]}}}