{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:14:30Z","timestamp":1783660470917,"version":"3.55.0"},"reference-count":137,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Antimicrobial resistance (AMR) and virulence have traditionally been viewed as competing traits in bacterial evolution due to fitness costs. However, Streptococcus pneumoniae has emerged as a paradigm of successful coevolution, with multidrug-resistant clones simultaneously maintaining or enhancing pathogenic potential. This review examines the molecular mechanisms, epidemiological patterns, and clinical consequences of the convergence between AMR and virulence in Streptococcus pneumoniae. Resistance to \u03b2-lactams is driven by mosaic penicillin-binding protein genes (pbp1a, pbp2b, pbp2x), while macrolide resistance is mediated primarily by the erm(B) gene (MLS phenotype) and mef(A\/E)\u2013msr(D) genes encoding an efflux system. These determinants are frequently co-localized on integrative and conjugative elements, ICEs, (e.g., Tn916 family) within successful clonal complexes such as CC271\/320 and lineages including ST320 and GPSC10. Contrary to the classical fitness cost hypothesis, compensatory epistasis, capsular recombination, metabolic adaptations, and intra-serotype phenotypic variation enable certain clones to combine high-level resistance to \u03b2-lactams, macrolides, and tetracyclines with enhanced colonization, biofilm formation, immune evasion, and invasive capacity. Post-pneumococcal conjugate vaccine (PCV) surveillance reveals the persistence and expansion of these high-risk lineages, contributing to treatment-refractory invasive pneumococcal disease (IPD), increased morbidity, and mortality. Although PCVs have reduced vaccine-type resistant strains in some settings, serotype replacement and emerging metabolic genotypes continue to drive adaptation. This review highlights the need for integrated genomic surveillance, novel therapeutics (e.g., omadacycline, lefamulin, endolysins), monoclonal antibodies, and next-generation vaccines targeting both resistance and conserved virulence determinants. A multifaceted strategy combining antimicrobial stewardship, strengthened surveillance, and innovative interventions is essential to curb the evolving threat of resistant and virulent S. pneumoniae.<\/jats:p>","DOI":"10.3390\/microorganisms14071451","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"1451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Convergence of Antimicrobial Resistance and Virulence in Streptococcus pneumoniae: A Molecular and Clinical Perspective"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3804-9550","authenticated-orcid":false,"given":"Jorge","family":"Almeida","sequence":"first","affiliation":[{"name":"Professional School of Pharmaceutical Biological Chemistry, University of Ixtlahuaca CUI, Ixtlahuaca 50740, Estado de M\u00e9xico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-2342","authenticated-orcid":false,"given":"Kenichi","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9466-9279","authenticated-orcid":false,"given":"Alejandra","family":"Ramirez-Villalva","sequence":"additional","affiliation":[{"name":"Professional School of Pharmaceutical Biological Chemistry, University of Ixtlahuaca CUI, Ixtlahuaca 50740, Estado de M\u00e9xico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0785-0889","authenticated-orcid":false,"given":"Ana G. Jop","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0129-3653","authenticated-orcid":false,"given":"Pedro Alejandro","family":"Fong-Coronado","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javian E.","family":"Ervin","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"},{"name":"Biomedical Sciences Master of Science Program, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8970-0035","authenticated-orcid":false,"given":"Gloria M.","family":"Casta\u00f1eda-Ruelas","sequence":"additional","affiliation":[{"name":"Faculty of Chemical and Biological Sciences, Autonomous University of Sinaloa, Culiacan 80013, Sinaloa, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge E.","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"},{"name":"Center for Immunology and Microbial Research, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tang, K.W.K., Millar, B.C., and Moore, J.E. (2023). Antimicrobial Resistance (AMR). Br. J. Biomed. Sci., 80.","DOI":"10.3389\/bjbs.2023.11387"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Salam, M.A., Al-Amin, M.Y., Salam, M.T., Pawar, J.S., Akhter, N., Rabaan, A.A., and Alqumber, M.A.A. (2023). Antimicrobial Resistance: A Growing Serious Threat for Global Public Health. Healthcare, 11.","DOI":"10.20944\/preprints202305.0555.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100947","DOI":"10.1016\/j.lanmic.2024.07.010","article-title":"Antimicrobial resistance: A concise update","volume":"6","author":"Ho","year":"2025","journal-title":"Lancet Microbe"},{"key":"ref_4","first-page":"71","article-title":"Antimicrobial Resistance in the Context of the Sustainable Development Goals: A Brief Review","volume":"11","author":"Gajdacs","year":"2021","journal-title":"Eur. J. Investig. Health Psychol. Educ."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Khan, Z.A., Siddiqui, M.F., and Park, S. (2019). Current and Emerging Methods of Antibiotic Susceptibility Testing. Diagnostics, 9.","DOI":"10.3390\/diagnostics9020049"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2475067","DOI":"10.1155\/2016\/2475067","article-title":"Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens","volume":"2016","author":"Santajit","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1056\/NEJMoa1914433","article-title":"Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012\u20132017","volume":"382","author":"Jernigan","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Karakonstantis, S., Ioannou, P., Samonis, G., and Kofteridis, D.P. (2021). Systematic Review of Antimicrobial Combination Options for Pandrug-Resistant Acinetobacter baumannii. Antibiotics, 10.","DOI":"10.3390\/antibiotics10111344"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gajic, I., Tomic, N., Lukovic, B., Jovicevic, M., Kekic, D., Petrovic, M., Jankovic, M., Trudic, A., Mitic Culafic, D., and Milenkovic, M. (2025). A Comprehensive Overview of Antibacterial Agents for Combating Multidrug-Resistant Bacteria: The Current Landscape, Development, Future Opportunities, and Challenges. Antibiotics, 14.","DOI":"10.3390\/antibiotics14030221"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S1473-3099(25)00118-5","article-title":"The WHO Bacterial Priority Pathogens List 2024: A prioritisation study to guide research, development, and public health strategies against antimicrobial resistance","volume":"25","author":"Sati","year":"2025","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.tim.2012.11.005","article-title":"Influence of bacterial interactions on pneumococcal colonization of the nasopharynx","volume":"21","author":"Shak","year":"2013","journal-title":"Trends Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","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":"ref_13","doi-asserted-by":"crossref","first-page":"7477","DOI":"10.1038\/s41467-023-43160-y","article-title":"The metabolic, virulence and antimicrobial resistance profiles of colonising Streptococcus pneumoniae shift after PCV13 introduction in urban Malawi","volume":"14","author":"Obolski","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Farrar, J.L., Childs, L., Ouattara, M., Akhter, F., Britton, A., Pilishvili, T., and Kobayashi, M. (2023). Systematic Review and Meta-Analysis of the Efficacy and Effectiveness of Pneumococcal Vaccines in Adults. Pathogens, 12.","DOI":"10.3390\/pathogens12050732"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhou, M., Wang, Z., Zhang, L., Kudinha, T., An, H., Qian, C., Jiang, B., Wang, Y., Xu, Y., and Liu, Z. (2021). Serotype Distribution, Antimicrobial Susceptibility, Multilocus Sequencing Type and Virulence of Invasive Streptococcus pneumoniae in China: A Six-Year Multicenter Study. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.798750"},{"key":"ref_16","unstructured":"Antimicrobial Resistance Collaborators (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet, 399, 629\u2013655."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e359","DOI":"10.1016\/S2214-109X(17)30043-8","article-title":"Effectiveness of the 13-valent pneumococcal conjugate vaccine against invasive pneumococcal disease in South African children: A case-control study","volume":"5","author":"Cohen","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e989","DOI":"10.1016\/S2214-109X(21)00165-0","article-title":"Impact and effectiveness of 13-valent pneumococcal conjugate vaccine on population incidence of vaccine and non-vaccine serotype invasive pneumococcal disease in Blantyre, Malawi, 2006\u20132018: Prospective observational time-series and case-control studies","volume":"9","author":"Swarthout","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e01792-15","DOI":"10.1128\/mBio.01792-15","article-title":"Nonencapsulated Streptococcus pneumoniae: Emergence and Pathogenesis","volume":"7","author":"Keller","year":"2016","journal-title":"mBio"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e0007026","DOI":"10.1128\/iai.00070-26","article-title":"Determinants of susceptibility and tolerance of Streptococcus pneumoniae to hypothiocyanous acid","volume":"94","author":"Rada","year":"2026","journal-title":"Infect. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gingerich, A.D., and Mousa, J.J. (2022). Diverse Mechanisms of Protective Anti-Pneumococcal Antibodies. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.824788"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Aceil, J., and Avci, F.Y. (2022). Pneumococcal Surface Proteins as Virulence Factors, Immunogens, and Conserved Vaccine Targets. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.832254"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00284-021-02715-2","article-title":"Comparative Genomic Analysis of Streptococcus pneumoniae Strains: Penicillin Non-susceptible Multi-drug-Resistant Serotype 19A Isolates","volume":"79","author":"Li","year":"2022","journal-title":"Curr. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127221","DOI":"10.1016\/j.micres.2022.127221","article-title":"Epidemiological characteristics and antibiotic resistance mechanisms of Streptococcus pneumoniae: An updated review","volume":"266","author":"Li","year":"2023","journal-title":"Microbiol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Senok, A., Thomsen, J., Abdulrazzaq, N.M., The UAE AMR Surveillance Consortium, Menezes, G.A., Ayoub Moubareck, C., and Everett, D. (2023). Antimicrobial resistance in Streptococcus pneumoniae: A retrospective analysis of emerging trends in the United Arab Emirates from 2010 to 2021. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1244357"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cilloniz, C., Martin-Loeches, I., Garcia-Vidal, C., San Jose, A., and Torres, A. (2016). Microbial Etiology of Pneumonia: Epidemiology, Diagnosis and Resistance Patterns. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122120"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Berbel, D., Gonzalez-Diaz, A., Lopez de Egea, G., Camara, J., and Ardanuy, C. (2022). An Overview of Macrolide Resistance in Streptococci: Prevalence, Mobile Elements and Dynamics. Microorganisms, 10.","DOI":"10.3390\/microorganisms10122316"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0005924","DOI":"10.1128\/jb.00059-24","article-title":"Biological puzzles solved by using Streptococcus pneumoniae: A historical review of the pneumococcal studies that have impacted medicine and shaped molecular bacteriology","volume":"206","author":"Hiller","year":"2024","journal-title":"J. Bacteriol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"ofad098","DOI":"10.1093\/ofid\/ofad098","article-title":"Trends in Streptococcus pneumoniae Antimicrobial Resistance in US Children: A Multicenter Evaluation","volume":"10","author":"Mohanty","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e0008225","DOI":"10.1128\/cmr.00082-25","article-title":"Streptococcus pneumoniae beta-lactam resistance: Epidemiological trends, molecular drivers, and innovative control strategies in the post-pandemic era","volume":"38","author":"Li","year":"2025","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhou, M., Wang, L., Wang, Z., Kudinha, T., Wang, Y., Xu, Y., and Liu, Z. (2022). Molecular Characterization of Penicillin-Binding Protein2x, 2b and 1a of Streptococcus pneumoniae Causing Invasive Pneumococcal Diseases in China: A Multicenter Study. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.838790"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1574-6976.2007.00095.x","article-title":"Penicillin-binding proteins and beta-lactam resistance","volume":"32","author":"Zapun","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1469-0691.2009.02724.x","article-title":"The antimicrobial resistance profile of Streptococcus pneumoniae","volume":"15","author":"Reinert","year":"2009","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1128\/CMR.00058-15","article-title":"Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: A United States Perspective","volume":"29","author":"Kim","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Abdel-Karim, S.A., Serry, F.M., Elmasry, E.M., and Hegazy, W.A.H. (2025). Phenotypic and genotypic characteristics of macrolide, lacosamide, and streptogramin resistance in clinically resistant Streptococci and their correlation with reduced biocide susceptibility. BMC Med., 23.","DOI":"10.1186\/s12916-025-04097-9"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Schroeder, M.R., and Stephens, D.S. (2016). Macrolide Resistance in Streptococcus pneumoniae. Front. Cell. Infect. Microbiol., 6.","DOI":"10.3389\/fcimb.2016.00098"},{"key":"ref_37","first-page":"756","article-title":"The Crisis of Macrolide Resistance in Pneumococci in Latin America","volume":"111","author":"Creel","year":"2024","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"397","DOI":"10.2217\/fmb-2021-0276","article-title":"A plain language summary of how lefamulin alone can be used to treat pneumonia caught outside of the hospital due to common bacterial causes, including drug-resistant bacteria","volume":"17","author":"Paukner","year":"2022","journal-title":"Future Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.45.1.1-12.2001","article-title":"Macrolide resistance conferred by base substitutions in 23S rRNA","volume":"45","author":"Vester","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chancey, S.T., Agrawal, S., Schroeder, M.R., Farley, M.M., Tettelin, H., and Stephens, D.S. (2015). Composite mobile genetic elements disseminating macrolide resistance in Streptococcus pneumoniae. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.00026"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1128\/AAC.01066-08","article-title":"New composite genetic element of the Tn916 family with dual macrolide resistance genes in a Streptococcus pneumoniae isolate belonging to clonal complex 271","volume":"53","author":"Camilli","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1086\/321001","article-title":"Structure and dissemination of a chromosomal insertion element encoding macrolide efflux in Streptococcus pneumoniae","volume":"184","author":"Gay","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e0054622","DOI":"10.1128\/spectrum.00546-22","article-title":"Characterization of Streptococcus pneumoniae Macrolide Resistance and Its Mechanism in Northeast China over a 20-Year Period","volume":"10","author":"Zhou","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Moshewh, S.M., Mohamed, S.E., Kumar, P., Eltom, A.E., Jagdale, S.R., Osman, E.A., Ahmed, S.S., Farajallah, N.A.M., and Ali, S. (2025). Efflux-Mediated Macrolide Resistance in Clinical Streptococcus Isolates: A Comparative Molecular Study. Antibiotics, 14.","DOI":"10.3390\/antibiotics14111148"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/j.1469-0691.2010.03182.x","article-title":"Changes in antimicrobial resistance, serotypes and genotypes in Streptococcus pneumoniae over a 30-year period","volume":"16","author":"Linares","year":"2010","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1128\/AAC.49.10.4203-4209.2005","article-title":"Macrolide efflux in Streptococcus pneumoniae is mediated by a dual efflux pump (mel and mef) and is erythromycin inducible","volume":"49","author":"Ambrose","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"a025320","DOI":"10.1101\/cshperspect.a025320","article-title":"Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance","volume":"6","author":"Hooper","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1093\/jac\/dkaf308","article-title":"Molecular characterization of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae susceptible to delafloxacin","volume":"80","author":"Cercenado","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zahari, N.I.N., Engku Abd Rahman, E.N.S., Irekeola, A.A., Ahmed, N., Rabaan, A.A., Alotaibi, J., Alqahtani, S.A., Halawi, M.Y., Alamri, I.A., and Almogbel, M.S. (2023). A Review of the Resistance Mechanisms for beta-Lactams, Macrolides and Fluoroquinolones among Streptococcus pneumoniae. Medicina, 59.","DOI":"10.3390\/medicina59111927"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ceyssens, P.J., Van Bambeke, F., Mattheus, W., Bertrand, S., Fux, F., Van Bossuyt, E., Damee, S., Nyssen, H.J., De Craeye, S., and Verhaegen, J. (2016). Molecular Analysis of Rising Fluoroquinolone Resistance in Belgian Non-Invasive Streptococcus pneumoniae Isolates (1995\u20132014). PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154816"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0923-2508(00)00167-4","article-title":"Mechanisms and spread of fluoroquinolone resistance in Streptococcus pneumoniae","volume":"151","author":"Varon","year":"2000","journal-title":"Res. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1093\/jac\/dks262","article-title":"Identification of a novel resistance mutation in parE that confers high-level resistance to moxifloxacin in Streptococcus pneumoniae","volume":"67","author":"Zhang","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Brooks, L.R.K., and Mias, G.I. (2018). Streptococcus pneumoniae\u2019s Virulence and Host Immunity: Aging, Diagnostics, and Prevention. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01366"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Liu, L., Wang, Y., Ge, L., Hu, D., Xiang, X., Fu, Y., Lu, J., Li, X., Yu, Y., and Tu, Y. (2023). Integrated genomic analysis of antibiotic resistance and virulence determinants in invasive strains of Streptococcus pneumoniae. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1238693"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e70447","DOI":"10.1002\/mco2.70447","article-title":"Antibiotic Resistance: A Genetic and Physiological Perspective","volume":"6","author":"Elbaiomy","year":"2025","journal-title":"MedComm"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.micinf.2012.01.012","article-title":"Streptococcus pneumoniae: The evolution of antimicrobial resistance to beta-lactams, fluoroquinolones and macrolides","volume":"14","author":"Cornick","year":"2012","journal-title":"Microbes Infect."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1017\/S0950268813000514","article-title":"Spread of multidrug-resistant clonal complex 271 of serotype 19F Streptococcus pneumoniae in Beijing, China: Characterization of serotype 19F","volume":"141","author":"Li","year":"2013","journal-title":"Epidemiol. Infect."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1093\/jac\/dkt332","article-title":"Evolution and molecular characterization of macrolide-resistant Streptococcus pneumoniae in Canada between 1998 and 2008","volume":"69","author":"Wierzbowski","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101138","DOI":"10.1016\/j.drup.2024.101138","article-title":"Ultrastructural, metabolic and genetic characteristics of determinants facilitating the acquisition of macrolide resistance by Streptococcus pneumoniae","volume":"77","author":"Wu","year":"2024","journal-title":"Drug Resist. Updat."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gonzales, B.E., Mercado, E.H., Pinedo-Bardales, M., Hinostroza, N., Campos, F., Chaparro, E., Del Aguila, O., Castillo, M.E., Saenz, A., and Reyes, I. (2022). Increase of Macrolide-Resistance in Streptococcus pneumoniae Strains After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Lima, Peru. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.866186"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Beheshti, M., Jabalameli, F., Feizabadi, M.M., Hahsemi, F.B., Beigverdi, R., and Emaneini, M. (2020). Molecular characterization, antibiotic resistance pattern and capsular types of invasive Streptococcus pneumoniae isolated from clinical samples in Tehran, Iran. BMC Microbiol., 20.","DOI":"10.1186\/s12866-020-01855-y"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"de Miguel, S., Perez-Abeledo, M., Ramos, B., Garcia, L., Arce, A., Martinez-Arce, R., Yuste, J., and Sanz, J.C. (2023). Evolution of Antimicrobial Susceptibility to Penicillin in Invasive Strains of Streptococcus pneumoniae during 2007\u20132021 in Madrid, Spain. Antibiotics, 12.","DOI":"10.3390\/antibiotics12020289"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Franjic Amancic, K., Mohar-Vitezic, B., Cekinovic Grbesa, D., Grubic Kezele, T., Abram, M., and Bubonja-Sonje, M. (2025). Molecular Epidemiology, Antimicrobial Resistance, and Clinical Characteristics of Streptococcus pneumoniae Isolated from Adult Patients with Invasive Pneumococcal Disease. Antibiotics, 14.","DOI":"10.3390\/antibiotics14111158"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12941-023-00565-3","article-title":"Genetic determinants of macrolide and tetracycline resistance in penicillin non-susceptible Streptococcus pneumoniae isolates from people living with HIV in Dar es Salaam, Tanzania","volume":"22","author":"Manyahi","year":"2023","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41579-024-01116-z","article-title":"Streptococcus pneumoniae epidemiology, pathogenesis and control","volume":"23","author":"Narciso","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s00430-024-00797-w","article-title":"Serotype distribution, antibiotic resistance, multilocus sequence typing, and virulence factors of invasive and non-invasive Streptococcus pneumoniae in Northeast China from 2000 to 2021","volume":"213","author":"Xu","year":"2024","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"127759","DOI":"10.1016\/j.vaccine.2025.127759","article-title":"Changes in the Streptococcus pneumoniae population responsible for invasive disease of young children after the implementation of conjugated vaccines in the National Immunization Program in Poland","volume":"64","author":"Golebiewska","year":"2025","journal-title":"Vaccine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jgar.2024.01.016","article-title":"A clade of Streptococcus pneumoniae clonal complex 320 with increased tolerance to beta-lactam antibiotics in a Chinese metropolitan city","volume":"36","author":"Yi","year":"2024","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Yan, Z., Miao, C., Liu, L., Fu, Y., Liu, X., Li, H., Kuang, L., Cui, Y., and Jiang, Y. (2024). Antibiotic susceptibility testing and molecular characterization based on whole-genome sequencing of Streptococcus pneumoniae isolates from pediatric infections at the National Regional Medical Center of Southwest China during the COVID-19 pandemic. Front. Public Health, 12.","DOI":"10.3389\/fpubh.2024.1490401"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Mokaddas, E., Asadzadeh, M., Syed, S., and Albert, M.J. (2024). High Prevalence of Novel Sequence Types in Streptococcus pneumoniae That Caused Invasive Diseases in Kuwait in 2018. Microorganisms, 12.","DOI":"10.3390\/microorganisms12010225"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e0407322","DOI":"10.1128\/spectrum.04073-22","article-title":"Pan-Genome-Wide Association Study of Serotype 19A Pneumococci Identifies Disease-Associated Genes","volume":"11","author":"Li","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/eva.12196","article-title":"The fitness costs of antibiotic resistance mutations","volume":"8","author":"Melnyk","year":"2015","journal-title":"Evol. Appl."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/emph\/eou032","article-title":"Limits to compensatory adaptation and the persistence of antibiotic resistance in pathogenic bacteria","volume":"2015","author":"MacLean","year":"2014","journal-title":"Evol. Med. Public Health"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1093\/genetics\/154.3.985","article-title":"Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria","volume":"154","author":"Levin","year":"2000","journal-title":"Genetics"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1128\/AAC.44.6.1575-1577.2000","article-title":"Relationship between capsular type, penicillin susceptibility, and virulence of human Streptococcus pneumoniae isolates in mice","volume":"44","author":"Rieux","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1086\/320992","article-title":"Complex relationship between acquisition of beta-lactam resistance and loss of virulence in Streptococcus pneumoniae","volume":"184","author":"Rieux","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Aguinagalde, L., Corsini, B., Domenech, A., Domenech, M., Camara, J., Ardanuy, C., Garcia, E., Linares, J., Fenoll, A., and Yuste, J. (2015). Emergence of Amoxicillin-Resistant Variants of Spain9V-ST156 Pneumococci Expressing Serotype 11A Correlates with Their Ability to Evade the Host Immune Response. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137565"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cels.2018.12.004","article-title":"Epistasis in a Fitness Landscape Defined by Antibody-Antigen Binding Free Energy","volume":"8","author":"Adams","year":"2019","journal-title":"Cell Syst."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e0282823","DOI":"10.1128\/mbio.02828-23","article-title":"Streptococcus pneumoniae favors tolerance via metabolic adaptation over resistance to circumvent fluoroquinolones","volume":"15","author":"Dao","year":"2024","journal-title":"mBio"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e189","DOI":"10.1093\/infdis\/jiae040","article-title":"Clonal Expansion of a Streptococcus pneumoniae Serotype 3 Capsule Variant Sequence Type 700 With Enhanced Vaccine Escape Potential After 13-Valent Pneumococcal Conjugate Vaccine Introduction","volume":"230","author":"Swarthout","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e735","DOI":"10.1016\/S2666-5247(22)00158-6","article-title":"Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: An international whole-genome sequencing study","volume":"3","author":"Lo","year":"2022","journal-title":"Lancet Microbe"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"002015","DOI":"10.1099\/jmm.0.002015","article-title":"Population structure, antibiotic resistance and molecular characteristics of Streptococcus pneumoniae causing invasive disease in Hubei, China","volume":"74","author":"Song","year":"2025","journal-title":"J. Med. Microbiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1016\/j.vaccine.2010.04.020","article-title":"Pneumococcal disease caused by serotype 19A: Review of the literature and implications for future vaccine development","volume":"28","author":"Reinert","year":"2010","journal-title":"Vaccine"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1473-3099(24)00588-7","article-title":"Serotype distribution of remaining invasive pneumococcal disease after extensive use of ten-valent and 13-valent pneumococcal conjugate vaccines (the PSERENADE project): A global surveillance analysis","volume":"25","author":"Peterson","year":"2025","journal-title":"Lancet Infect. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Dietl, B., Henares, D., Boix-Palop, L., Munoz-Almagro, C., Garau, J., and Calbo, E. (2021). Related Factors to Streptococcus pneumoniae Invasive Infection and Clinical Manifestations: The Potential Role of Nasopharyngeal Microbiome. Front. Med., 8.","DOI":"10.3389\/fmed.2021.650271"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1128\/AAC.44.11.3137-3143.2000","article-title":"Biological cost of AmpC production for Salmonella enterica serotype Typhimurium","volume":"44","author":"Morosini","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.2147\/IDR.S519795","article-title":"Pan-Genome-Wide Association Study Identifies Genetic Factors Associated with the Pathogenicity of Invasive Serotype 19F Streptococcus Pneumoniae","volume":"18","author":"Shi","year":"2025","journal-title":"Infect. Drug Resist."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Lei, Z., Liu, Q., Ma, Y., Yang, X., Zu, H., Li, Z., Zhang, F., Pu, D., Zhang, Y., and Lu, B. (2025). In-vitro antimicrobial activity of new antimicrobial agents against Streptococcus pneumoniae and potential resistance mechanisms: A multicenter study. BMC Microbiol., 25.","DOI":"10.1186\/s12866-025-03967-9"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e0078523","DOI":"10.1128\/aac.00785-23","article-title":"Comparison of contemporary invasive and non-invasive Streptococcus pneumoniae isolates reveals new insights into circulating anti-microbial resistance determinants","volume":"67","author":"Higgs","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"ofac420","DOI":"10.1093\/ofid\/ofac420","article-title":"A Multicenter Evaluation of Trends in Antimicrobial Resistance Among Streptococcus pneumoniae Isolates From Adults in the United States","volume":"9","author":"Mohanty","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_91","first-page":"e000299","article-title":"Genomic differences among carriage and invasive nontypeable pneumococci circulating in South Africa","volume":"5","author":"Mohale","year":"2019","journal-title":"Microb. Genom."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1128\/JCM.39.5.1827-1832.2001","article-title":"Persistence of two invasive Streptococcus pneumoniae clones of serotypes 1 and 5 in comparison to that of multiple clones of serotypes 6B and 23F among children in southern Israel","volume":"39","author":"Porat","year":"2001","journal-title":"J. Clin. Microbiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1128\/IAI.69.6.3755-3761.2001","article-title":"Requirement for capsule in colonization by Streptococcus pneumoniae","volume":"69","author":"Magee","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1128\/IAI.00755-12","article-title":"PspK of Streptococcus pneumoniae increases adherence to epithelial cells and enhances nasopharyngeal colonization","volume":"81","author":"Keller","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ijid.2021.02.109","article-title":"Clonal lineages and antimicrobial resistance of nonencapsulated Streptococcus pneumoniae in the post-pneumococcal conjugate vaccine era in Japan","volume":"105","author":"Kawaguchiya","year":"2021","journal-title":"Int. J. Infect. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1128\/AAC.01242-13","article-title":"In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline","volume":"58","author":"Macone","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6409","DOI":"10.1016\/j.bmc.2016.07.029","article-title":"Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic","volume":"24","author":"Tanaka","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e02262-18","DOI":"10.1128\/AAC.02262-18","article-title":"Antimicrobial Activity of Omadacycline Tested against Clinical Bacterial Isolates from Hospitals in Mainland China, Hong Kong, and Taiwan: Results from the SENTRY Antimicrobial Surveillance Program (2013 to 2016)","volume":"63","author":"Carvalhaes","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1056\/NEJMoa1800201","article-title":"Omadacycline for Community-Acquired Bacterial Pneumonia","volume":"380","author":"Stets","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"103656","DOI":"10.1016\/j.eclinm.2025.103656","article-title":"Omadacycline versus moxifloxacin for community-acquired bacterial pneumonia (OPTIC-2): A phase 3b, randomised, double-blind, multicentre, controlled, noninferiority trial","volume":"90","author":"File","year":"2025","journal-title":"EClinicalMedicine"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1007\/s10096-019-03590-3","article-title":"Eravacycline, a newly approved fluorocycline","volume":"38","author":"Lee","year":"2019","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e01715-19","DOI":"10.1128\/AAC.01715-19","article-title":"In Vitro Activity of Eravacycline against Gram-Positive Bacteria Isolated in Clinical Laboratories Worldwide from 2013 to 2017","volume":"64","author":"Morrissey","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"a027110","DOI":"10.1101\/cshperspect.a027110","article-title":"Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance","volume":"7","author":"Paukner","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1128\/AAC.00627-16","article-title":"In Vitro Activity of Lefamulin Tested against Streptococcus pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States","volume":"60","author":"Mendes","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1093\/jac\/dkad389","article-title":"7-Year (2015\u20132021) longitudinal surveillance of lefamulin in vitro activity against bacterial pathogens collected worldwide from patients with respiratory tract infections including pneumonia and characterization of resistance mechanisms","volume":"79","author":"Paukner","year":"2024","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jgar.2021.10.021","article-title":"Pooled microbiological findings and efficacy outcomes by pathogen in adults with community-acquired bacterial pneumonia from the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 phase 3 trials of lefamulin versus moxifloxacin","volume":"29","author":"Paukner","year":"2022","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4915","DOI":"10.1128\/AAC.00078-09","article-title":"In vitro activity of nemonoxacin, a novel nonfluorinated quinolone, against 2440 clinical isolates","volume":"53","author":"Adam","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_108","first-page":"163","article-title":"Streptococcus pneumoniae and its bacteriophages: One long argument","volume":"7","author":"Lopez","year":"2004","journal-title":"Int. Microbiol."},{"key":"ref_109","doi-asserted-by":"crossref","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":"ref_110","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1128\/AAC.49.3.1225-1228.2005","article-title":"Synergistic killing of Streptococcus pneumoniae with the bacteriophage lytic enzyme Cpl-1 and penicillin or gentamicin depends on the level of penicillin resistance","volume":"49","author":"Djurkovic","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s10020-025-01226-1","article-title":"Bacteriophage-derived endolysins restore antibiotic susceptibility in beta-lactam- and macrolide-resistant Streptococcus pneumoniae infections","volume":"31","author":"Farmen","year":"2025","journal-title":"Mol. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e02212-17","DOI":"10.1128\/AAC.02212-17","article-title":"Chemotherapy with Phage Lysins Reduces Pneumococcal Colonization of the Respiratory Tract","volume":"62","author":"Corsini","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_113","doi-asserted-by":"crossref","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":"ref_114","doi-asserted-by":"crossref","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":"ref_115","doi-asserted-by":"crossref","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":"ref_116","doi-asserted-by":"crossref","first-page":"102145","DOI":"10.1016\/j.omtn.2024.102145","article-title":"Synthetic mRNA delivered to human cells leads to expression of Cpl-1 bacteriophage-endolysin with activity against Streptococcus pneumoniae","volume":"35","author":"Jansson","year":"2024","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_117","doi-asserted-by":"crossref","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":"ref_118","doi-asserted-by":"crossref","first-page":"4534","DOI":"10.1128\/IAI.72.8.4534-4540.2004","article-title":"Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin","volume":"72","author":"Florez","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1128\/iai.64.2.480-484.1996","article-title":"Functional analysis of pneumolysin by use of monoclonal antibodies","volume":"64","author":"Mendez","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"e0027725","DOI":"10.1128\/spectrum.00277-25","article-title":"In vitro and in vivo evaluation of humanized monoclonal antibodies targeting pneumolysin","volume":"13","author":"Song","year":"2025","journal-title":"Microbiol. Spectr."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/21645515.2017.1403698","article-title":"Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism","volume":"14","author":"Visan","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e00747-20","DOI":"10.1128\/IAI.00747-20","article-title":"Broadly Reactive Human Monoclonal Antibodies Targeting the Pneumococcal Histidine Triad Protein Protect against Fatal Pneumococcal Infection","volume":"89","author":"Huang","year":"2021","journal-title":"Infect. Immun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1128\/IAI.06081-11","article-title":"A serotype 3 pneumococcal capsular polysaccharide-specific monoclonal antibody requires Fcgamma receptor III and macrophages to mediate protection against pneumococcal pneumonia in mice","volume":"80","author":"Weber","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"e0144621","DOI":"10.1128\/Spectrum.01446-21","article-title":"Isolation and Characterization of Human Monoclonal Antibodies to Pneumococcal Capsular Polysaccharide 3","volume":"9","author":"Babb","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1128\/AAC.00769-09","article-title":"Generic and specific adaptive responses of Streptococcus pneumoniae to challenge with three distinct antimicrobial peptides, bacitracin, LL-37, and nisin","volume":"54","author":"Majchrzykiewicz","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1128\/AAC.01756-09","article-title":"Human antimicrobial peptide LL-37 induces MefE\/Mel-mediated macrolide resistance in Streptococcus pneumoniae","volume":"54","author":"Zahner","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e202100189","DOI":"10.1002\/jbio.202100189","article-title":"Photodynamic inactivation of Streptococcus pneumoniae with external illumination at 808 nm through the ex vivo porcine thoracic cage","volume":"15","author":"Kassab","year":"2022","journal-title":"J. Biophotonics"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e450","DOI":"10.1016\/S2666-5247(21)00064-1","article-title":"Antimicrobial resistance in paediatric Streptococcus pneumoniae isolates amid global implementation of pneumococcal conjugate vaccines: A systematic review and meta-regression analysis","volume":"2","author":"Andrejko","year":"2021","journal-title":"Lancet Microbe"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"101513","DOI":"10.1016\/j.nmni.2024.101513","article-title":"Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolated from children in Japan, 2023","volume":"62","author":"Kawaguchiya","year":"2024","journal-title":"New Microbes New Infect."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1093\/jac\/dkaf085","article-title":"Comparing serotype coverage of pneumococcal vaccines with PCV21 (V116), a new 21-valent conjugate pneumococcal vaccine, and the epidemiology of its eight unique Streptococcus pneumoniae serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) causing invasive pneumococcal disease in adult patients in Canada: SAVE study, 2018\u20132021","volume":"80","author":"Schellenberg","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Morais, V., Texeira, E., and Suarez, N. (2019). Next-Generation Whole-Cell Pneumococcal Vaccine. Vaccines, 7.","DOI":"10.3390\/vaccines7040151"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1016\/j.vaccine.2024.01.104","article-title":"Immunization with a whole cell vaccine reduces pneumococcal nasopharyngeal density and shedding, and middle ear infection in mice","volume":"42","author":"Manning","year":"2024","journal-title":"Vaccine"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/S1473-3099(23)00572-8","article-title":"Evaluating the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults aged 18 to 64 years: A phase 1\/2, double-masked, dose-finding, active-controlled, randomised clinical trial","volume":"24","author":"Wassil","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.molmed.2021.07.008","article-title":"Host-informed therapies for the treatment of pneumococcal pneumonia","volume":"27","author":"Sundaresh","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1007\/s13346-024-01708-5","article-title":"Pneumolysin-responsive liposomal platform for selective treatment of Streptococcus pneumoniae","volume":"15","author":"Watt","year":"2025","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e0049722","DOI":"10.1128\/spectrum.00497-22","article-title":"Antimicrobial Activity of Peptide-Coupled Antisense Peptide Nucleic Acids in Streptococcus pneumoniae","volume":"10","author":"Barkowsky","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1093\/cid\/ciz1183","article-title":"Impact of a Comprehensive Antimicrobial Stewardship Program on Institutional Burden of Antimicrobial Resistance: A 14-Year Controlled Interrupted Time-series Study","volume":"71","author":"Peragine","year":"2020","journal-title":"Clin. Infect. Dis."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/7\/1451\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:34:55Z","timestamp":1783658095000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/7\/1451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":137,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["microorganisms14071451"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14071451","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}