{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T23:51:05Z","timestamp":1780357865754,"version":"3.54.1"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p><jats:italic>Streptococcus pneumoniae<\/jats:italic> is responsible for causing a range of diseases, from self-limiting otitis media to more severe disease such as pneumonia, sepsis, and meningitis. Vaccines and antibiotics have successfully decreased this disease burden; however, serotype replacement due to vaccines and antibiotic resistance remain issues pointing to the need for further research into alternative methods of treatment. <jats:italic>S. pneumoniae<\/jats:italic> continues to pose a global threat to young children and the elderly. Endolysins, which function as peptidoglycan hydrolases, are an attractive alternative treatment given their rapid bactericidal activity, specificity, and lack of noted resistance. This review considers the uses of endolysins within the main niches of infection for <jats:italic>S. pneumoniae<\/jats:italic>: pulmonary, middle ear, and the bloodstream and central nervous system. Therapeutic hurdles, such as delivery and mechanical barrier challenges, are discussed and endolysin-focused solutions to circumvent these challenges are proposed. The ability to address niche-specific hurdles using endolysins will allow for an increase in effective therapies against <jats:italic>S. pneumoniae.<\/jats:italic><\/jats:p>","DOI":"10.3389\/fmicb.2025.1660791","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:29:53Z","timestamp":1759469393000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Endolysins: targeting Streptococcus pneumoniae in its major anatomical niches of infection and addressing the hurdles"],"prefix":"10.3389","volume":"16","author":[{"given":"Giovanna","family":"Castallanos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Gonzalez-Juarbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3390\/antibiotics10020124","article-title":"Phage-encoded endolysins","volume":"10","author":"Abdelrahman","year":"2021","journal-title":"Antibiotics"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3184\/003685016X14627913637705","article-title":"Bacteriophage endolysins and their applications","volume":"99","author":"Ajuebor","year":"2016","journal-title":"Sci. Prog."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1089\/ars.2016.6691","article-title":"Advanced age alters monocyte and macrophage responses","volume":"25","author":"Albright","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0006924","DOI":"10.1128\/mbio.00069-24","article-title":"SP-CHAP, an endolysin with enhanced activity against biofilm pneumococci and nasopharyngeal colonization","volume":"15","author":"Alreja","year":"2024","journal-title":"MBio"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12890-022-02301-7","article-title":"The burden of lower respiratory infections and their underlying etiologies in the Middle East and North Africa region, 1990-2019: results from the global burden of disease study 2019","volume":"23","author":"Ashrafi-Asgarabad","year":"2023","journal-title":"BMC Pulm. Med."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1093\/clinids\/3.2.183","article-title":"Pneumococcus: the first one hundred years","volume":"3","author":"Austrian","year":"1981","journal-title":"Rev. Infect. Dis."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"25063","DOI":"10.1038\/srep25063","article-title":"Triple-acting lytic enzyme treatment of drug-resistant and intracellular Staphylococcus aureus","volume":"6","author":"Becker","year":"2016","journal-title":"Sci. Rep."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"15021","DOI":"10.1038\/mtm.2015.21","article-title":"Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance","volume":"2","author":"Blazanovic","year":"2015","journal-title":"Mol. The.r Methods Clin. Dev."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/S1473-3099(04)00938-7","article-title":"Streptococcus pneumoniae colonisation: the key to pneumococcal disease","volume":"4","author":"Bogaert","year":"2004","journal-title":"Lancet Infect. Dis."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.peptides.2016.11.011","article-title":"In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides","volume":"87","author":"Bolhassani","year":"2017","journal-title":"Peptides"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.3389\/fimmu.2018.01366","article-title":"Streptococcus pneumoniae's virulence and host immunity: aging, diagnostics, and prevention","volume":"9","author":"Brooks","year":"2018","journal-title":"Front. Immunol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e0240535","DOI":"10.1371\/journal.pone.0240535","article-title":"Controlled release of ciprofloxacin and ceftriaxone from a single ototopical administration of antibiotic-loaded polymer microspheres and thermoresponsive gel","volume":"15","author":"Bruk","year":"2020","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"16","DOI":"10.3109\/09513590.2013.852531","article-title":"The immune system and aging: a review","volume":"30","author":"Castelo-Branco","year":"2014","journal-title":"Gynecol. Endocrinol."},{"key":"ref14","first-page":"258","article-title":"Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children - advisory committee on immunization practices (ACIP)","volume":"59","year":"2010","journal-title":"MMWR Morb. Mortal Wkly. Rep."},{"key":"ref15","volume-title":"Active Bacterial Core Surveillance Report, Emerging Infections Program Network,","year":"2018"},{"key":"ref16","volume-title":"Antibiotic resistance threats in the United States, 2019","year":"2019"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-3-319-78538-7_2","article-title":"Antimicrobial resistance among Streptocccus pneumoniae","volume-title":"Antimicrobial resistance in the 21st century","author":"Cilloniz","year":"2018"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"eabm4065","DOI":"10.1126\/scitranslmed.abm4065","article-title":"Polysaccharide and conjugate vaccines to Streptococcus pneumoniae generate distinct humoral responses","volume":"14","author":"Davies","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"8125","DOI":"10.1073\/pnas.87.20.8125","article-title":"Chimeric phage-bacterial enzymes: a clue to the modular evolution of genes","volume":"87","author":"Diaz","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"5355","DOI":"10.1128\/AAC.01372-13","article-title":"Improving the lethal effect of cpl-7, a pneumococcal phage lysozyme with broad bactericidal activity, by inverting the net charge of its cell wall-binding module","volume":"57","author":"Diez-Martinez","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1093\/jac\/dkv038","article-title":"A novel chimeric phage lysin with high in vitro and in vivo bactericidal activity against Streptococcus pneumoniae","volume":"70","author":"D\u00edez-Mart\u00ednez","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1093\/jac\/dkt131","article-title":"Delivery of the endolysin Cpl-1 by inhalation rescues mice with fatal pneumococcal pneumonia","volume":"68","author":"Doehn","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"4789","DOI":"10.1128\/AAC.49.11.4789-4792.2005","article-title":"Therapeutic effects of bacteriophage Cpl-1 lysin against Streptococcus pneumoniae endocarditis in rats","volume":"49","author":"Entenza","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"611367","DOI":"10.3389\/fmolb.2021.611367","article-title":"A nanomule peptide carrier delivers siRNA across the intact blood-brain barrier to attenuate ischemic stroke","volume":"8","author":"Eyford","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.2147\/IJN.S218966","article-title":"Antimicrobial peptide-loaded nanoparticles as inhalation therapy for Pseudomonas aeruginosa infections","volume":"15","author":"Falciani","year":"2020","journal-title":"Int. J. Nanomedicine"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.ijmm.2010.04.002","article-title":"Bacteriophage endolysins: a novel anti-infective to control gram-positive pathogens","volume":"300","author":"Fischetti","year":"2010","journal-title":"Int. J. Med. Microbiol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"3750","DOI":"10.1172\/JCI136577","article-title":"Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis","volume":"130","author":"Fowler","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/0378-1119(90)90116-9","article-title":"Modular organization of the lytic enzymes of Streptococcus pneumoniae and its bacteriophages","volume":"86","author":"Garcia","year":"1990","journal-title":"Gene"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"118850","DOI":"10.1016\/j.ijpharm.2019.118850","article-title":"Comprehensive evaluation of chitosan nanoparticle based phage lysin delivery system; a novel approach to counter S. pneumoniae infections","volume":"573","author":"Gondil","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1086\/587942","article-title":"Phage lytic enzyme Cpl-1 for antibacterial therapy in experimental pneumococcal meningitis","volume":"197","author":"Grandgirard","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"6330","DOI":"10.1016\/j.vaccine.2016.10.052","article-title":"Post-licensure surveillance of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged \u2a7e19years old in the United States, vaccine adverse event reporting system (VAERS), June 1, 2012-December 31, 2015","volume":"34","author":"Haber","year":"2016","journal-title":"Vaccine"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1075774","DOI":"10.3389\/fimmu.2023.1075774","article-title":"Immunogenic epitope scanning in bacteriolytic enzymes pal and Cpl-1 and engineering pal to escape antibody responses","volume":"14","author":"Harhala","year":"2023","journal-title":"Front. Immunol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1093\/jac\/dkg485","article-title":"Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model","volume":"52","author":"Jado","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"611","DOI":"10.3390\/pharmaceutics16121611","article-title":"Drug delivery across the blood-brain barrier: a new strategy for the treatment of neurological diseases","volume":"16","author":"Jiao","year":"2024","journal-title":"Pharmaceutics"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1128\/AAC.02629-16","article-title":"Pharmacokinetics and tolerance of the phage endolysin-based candidate drug SAL200 after a single intravenous administration among healthy volunteers","volume":"61","author":"Jun","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/nrmicro1871","article-title":"The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease","volume":"6","author":"Kadioglu","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s40780-024-00367-5","article-title":"Antibiotic therapy for bacterial pneumonia","volume":"10","author":"Kato","year":"2024","journal-title":"J. Pharm Health Care Sci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e01792","DOI":"10.1128\/mBio.01792-15","article-title":"Nonencapsulated Streptococcus pneumoniae: emergence and pathogenesis","volume":"7","author":"Keller","year":"2016","journal-title":"MBio"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"0049","DOI":"10.34133\/bmr.0049","article-title":"Polyacrylamide\/gel-based self-healing artificial tympanic membrane for drug delivery of otitis treatment","volume":"28","author":"Kim","year":"2024","journal-title":"Biomater Res."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"793","DOI":"10.15585\/mmwr.mm7336a3","article-title":"Use of 21-valent pneumococcal conjugate vaccine among U.S. adults: recommendations of the advisory committee on immunization practices - United States, 2024","volume":"73","author":"Kobayashi","year":"2024","journal-title":"MMWR Morb. Mortal Wkly. Rep."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1080\/08927014.2021.1887151","article-title":"The novel endolysin XZ.700 effectively treats MRSA biofilms in two biofilm models without showing toxicity on human bone cells in vitro","volume":"37","author":"Kuiper","year":"2021","journal-title":"Biofouling"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1080\/1061186X.2017.1347791","article-title":"Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study","volume":"26","author":"Kurabi","year":"","journal-title":"J. Drug Target."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"11815","DOI":"10.1038\/s41598-018-30031-6","article-title":"Active transport of peptides across the intact human tympanic membrane","volume":"8","author":"Kurabi","year":"","journal-title":"Sci. Rep."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"2463427","DOI":"10.1080\/10717544.2025.2463427","article-title":"Peptides rapidly transport antibiotic across the intact tympanic membrane to treat a middle ear infection","volume":"32","author":"Kurabi","year":"2025","journal-title":"Drug Deliv."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1093\/infdis\/jit139","article-title":"The immune response to pneumococcal polysaccharides 14 and 23F among elderly individuals consists predominantly of switched memory B cells","volume":"208","author":"Leggat","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"760","DOI":"10.3390\/v16050760","article-title":"Influence of lipopolysaccharide-lnteracting peptides fusion with endolysin LysECD7 and fatty acid derivatization on the efficacy against Acinetobacter baumannii infection in vitro and in vivo","volume":"16","author":"Li","year":"2024","journal-title":"Viruses"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"6310","DOI":"10.1039\/d4bm00983e","article-title":"Transtympanic delivery of V2O5 nanowires with a tympanic-membrane penetrating peptide","volume":"12","author":"Liu","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/S1473-3099(19)30297-X","article-title":"Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study","volume":"19","author":"Lo","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"6199","DOI":"10.1128\/IAI.71.11.6199-6204.2003","article-title":"Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia","volume":"71","author":"Loeffler","year":"2003","journal-title":"Infect. Immun."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"2170","DOI":"10.1126\/science.1066869","article-title":"Rapid killing of Streptococcus pneumoniae with a bacteriophage cell wall hydrolase","volume":"294","author":"Loeffler","year":"2001","journal-title":"Science"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1128\/microbiolspec.GPP1123-0004-2018","article-title":"Streptococcus pneumoniae: invasion and inflammation","volume":"7","author":"Loughran","year":"2019","journal-title":"Microbiol. Spectr."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1128\/AAC.00311-20","article-title":"A choline-recognizing monomeric lysin, ClyJ-3m, shows elevated activity against Streptococcus pneumoniae","volume":"64","author":"Luo","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"7318","DOI":"10.1128\/IAI.69.12.7318-7325.2001","article-title":"Streptococcus pneumoniae causes experimental meningitis following intranasal and otitis media infections via a nonhematogenous route","volume":"69","author":"Marra","year":"2001","journal-title":"Infect. Immun."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"e28","DOI":"10.1371\/journal.ppat.0030028","article-title":"Novel strategy to prevent otitis media caused by colonizing Streptococcus pneumoniae","volume":"3","author":"McCullers","year":"2007","journal-title":"PLoS Pathog."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3390\/pharmaceutics9040053","article-title":"An overview of chitosan nanoparticles and its application in non-parenteral drug delivery","volume":"9","author":"Mohammed","year":"2017","journal-title":"Pharmaceutics"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/B978-0-12-394438-2.00007-4","article-title":"Endolysins as antimicrobials","volume":"83","author":"Nelson","year":"2012","journal-title":"Adv. Virus Res."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"292","DOI":"10.3390\/v10060292","article-title":"Phage-derived peptidoglycan degrading enzymes: challenges and future prospects for in vivo therapy","volume":"10","author":"Oliveira","year":"2018","journal-title":"Viruses"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s40121-022-00588-x","article-title":"Estimates of the health and economic burden of pneumococcal infections attributable to the 15-valent pneumococcal conjugate vaccine serotypes in the USA","volume":"11","author":"Owusu-Edusei","year":"2022","journal-title":"Infect. Dis. Ther."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3389\/fncel.2019.00261","article-title":"Inner ear therapeutics: an overview of middle ear delivery","volume":"13","author":"Patel","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12951-018-0392-8","article-title":"Nano based drug delivery systems: recent developments and future prospects","volume":"16","author":"Patra","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2147\/IDR.S39637","article-title":"Update on otitis media - prevention and treatment","volume":"7","author":"Qureishi","year":"2014","journal-title":"Infect. Drug Resist."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jconrel.2013.12.026","article-title":"Chitosan nanoparticles for siRNA delivery: optimizing formulation to increase stability and efficiency","volume":"176","author":"Ragelle","year":"2014","journal-title":"J. Control. Release"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3390\/antibiotics10111277","article-title":"Endolysin, a promising solution against antimicrobial resistance","volume":"10","author":"Rahman","year":"2021","journal-title":"Antibiotics"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.ijantimicag.2011.08.009","article-title":"A stable phage lysin (Cpl-1) dimer with increased antipneumococcal activity and decreased plasma clearance","volume":"38","author":"Resch","year":"2011","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"e1062590","DOI":"10.1080\/21597081.2015.1062590","article-title":"Antimicrobial bacteriophage-derived proteins and therapeutic applications","volume":"5","author":"Roach","year":"2015","journal-title":"Bacteriophage"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"G2","DOI":"10.1016\/j.vaccine.2008.11.005","article-title":"The burden of otitis media","volume":"26","author":"Rovers","year":"2008","journal-title":"Vaccine"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/S0140-6736(04)15495-0","article-title":"Otitis media","volume":"363","author":"Rovers","year":"2004","journal-title":"Lancet"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"e0261720","DOI":"10.1371\/journal.pone.0261720","article-title":"Inhaled ciprofloxacin-loaded poly(2-ethyl-2-oxazoline) nanoparticles from dry powder inhaler formulation for the potential treatment of lower respiratory tract infections","volume":"16","author":"Sabuj","year":"2021","journal-title":"PLoS One"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.copbio.2020.09.012","article-title":"Bacteriophage endolysins - extending their application to tissues and the bloodstream","volume":"68","author":"Schmelcher","year":"2021","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.3389\/fmicb.2018.02927","article-title":"Improved biodistribution and extended serum half-life of a bacteriophage endolysin by albumin binding domain fusion","volume":"9","author":"Seijsing","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s41479-016-0007-9","article-title":"Anatomical site-specific contributions of pneumococcal virulence determinants","volume":"8","author":"Shenoy","year":"2016","journal-title":"Pneumonia"},{"key":"ref72","volume-title":"Development of a new approach to control otitis media pathogens PhD in Biomedical Engineering","author":"Silva","year":"2022"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"121752","DOI":"10.1016\/j.ijpharm.2022.121752","article-title":"Ex vivo transtympanic permeation of the liposome encapsulated S. pneumoniae endolysin MSlys","volume":"620","author":"Silva","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1128\/CVI.00110-08","article-title":"Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins","volume":"15","author":"Simell","year":"2008","journal-title":"Clin. Vaccine Immunol."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s43586-024-00377-5","article-title":"Phage therapy","volume":"5","author":"Skurnik","year":"2025","journal-title":"Nat. Rev. Methods Primers"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"e0266928","DOI":"10.1371\/journal.pone.0266928","article-title":"Efficacy assessment of a novel endolysin PlyAZ3aT for the treatment of ceftriaxone-resistant pneumococcal meningitis in an infant rat model","volume":"17","author":"Valente","year":"2022","journal-title":"PLoS One"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"e744","DOI":"10.1016\/S2214-109X(18)30247-X","article-title":"Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15","volume":"6","author":"Wahl","year":"2018","journal-title":"Lancet Glob. Health"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"122679","DOI":"10.1016\/j.ijpharm.2023.122679","article-title":"Bacteriophage endolysin powders for inhaled delivery against pulmonary infections","volume":"635","author":"Wang","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"119982","DOI":"10.1016\/j.ijpharm.2020.119982","article-title":"Can bacteriophage endolysins be nebulised for inhalation delivery against Streptococcus pneumoniae?","volume":"591","author":"Wang","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41579-018-0001-8","article-title":"Streptococcus pneumoniae: transmission, colonization and invasion","volume":"16","author":"Weiser","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref81","first-page":"51","article-title":"Immune responses to pneumococcal vaccines in children and adults: rationale for age-specific vaccination","volume":"3","author":"Westerink","year":"2012","journal-title":"Aging Dis."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"e0184221","DOI":"10.1128\/AAC.01842-21","article-title":"A phase 1 study to evaluate safety and pharmacokinetics following administration of single and multiple doses of the antistaphylococcal lysin LSVT-1701 in healthy adult subjects","volume":"66","author":"Wire","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1097\/CCM.0b013e31819586a6","article-title":"Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia","volume":"37","author":"Witzenrath","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"e02043","DOI":"10.1128\/AAC.02043-18","article-title":"ClyJ is a novel pneumococcal chimeric lysin with a cysteine- and histidine-dependent amidohydrolase\/peptidase catalytic domain","volume":"63","author":"Yang","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"1526096","DOI":"10.3389\/fmicb.2025.1526096","article-title":"Novel delivery systems for phages and lysins in the topical management of wound infections: a narrative review","volume":"16","author":"Yang","year":"2025","journal-title":"Front. Microbiol."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"e01610","DOI":"10.1128\/AAC.01610-19","article-title":"Linker editing of pneumococcal lysin ClyJ conveys improved bactericidal activity","volume":"64","author":"Yang","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.chembiol.2015.04.017","article-title":"Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo","volume":"22","author":"Zhao","year":"2015","journal-title":"Chem. Biol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1660791\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:29:55Z","timestamp":1759469395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1660791\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,3]]},"references-count":87,"alternative-id":["10.3389\/fmicb.2025.1660791"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1660791","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,3]]},"article-number":"1660791"}}