{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:03:13Z","timestamp":1786719793661,"version":"build-2736575974"},"reference-count":75,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty of Science at the University of Regina"},{"name":"Canada Research Chair in Chemogenomics and Antimicrobial Research"},{"name":"Natural Science and Engineering Research Council"},{"name":"Cystic Fibrosis Canada Early Career Investigator Award"},{"name":"Faculty of Graduate Studies and Research at the University of Regina"},{"name":"Saskatchewan Health Research Foundation establishment grant"},{"name":"Canada Foundation for Innovation and Innovation Saskatchewan grants"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Staphylococcus aureus is the most common bacterial pathogen affecting pediatric patients with cystic fibrosis (CF), a genetic disorder that causes thick mucus buildup in the lungs, providing a scaffold for chronic infections. Antibiotic treatment is typically guided by standard in vitro antimicrobial susceptibility testing (AST) in Mueller-Hinton broth (MHB), which does not represent the infection site in CF lungs. Notably, discordances between AST predictions and antibiotic therapeutic outcomes have been reported in up to 50% of CF cases. To address this gap, we conducted ASTs against methicillin-resistant S. aureus (MRSA) in CF sputum-mimetic media compared with MHB, demonstrating \u2265 4-fold discordances across four of nine antibiotic classes. Most significantly, we observed unexpected \u03b2-lactam sensitization of MRSA strains (up to 128-fold) in CF sputum-like media, crossing the clinical breakpoint, suggesting this shift may alter therapeutic outcomes. Genome-wide screens and follow-up assays revealed underlying cell envelope remodeling and alterations to cell envelope stress responses. On the other hand, mucin binding to daptomycin may have led to an apparent 8-fold increase in resistance to this antibiotic in one of the CF sputum-like media. Overall, our AST results in CF sputum-mimetic conditions provide insights into bacterial responses during CF infections. Importantly, they suggest \u03b2-lactams may be effective in treating MRSA infections in CF patients, warranting further investigation in relevant in vivo systems.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00319","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:21:30Z","timestamp":1785849690000},"page":"2763-2777","source":"Crossref","is-referenced-by-count":0,"title":["Clinically Relevant\nAltered Antibiotic Responses and\nMechanisms of \u03b2-Lactam Sensitization of MRSA in Cystic\nFibrosis Artificial Sputum"],"prefix":"10.1021","volume":"12","author":[{"given":"Tyler J.","family":"Hamelin","sequence":"first","affiliation":[{"name":"University of Regina , , , ,","place":["Regina, Saskatchewan, Canada, S4S 0A2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Molaeitabari","sequence":"additional","affiliation":[{"name":"University of Regina , , , ,","place":["Regina, Saskatchewan, Canada, S4S 0A2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4012-2339","authenticated-orcid":true,"given":"Marc R.","family":"MacKinnon","sequence":"additional","affiliation":[{"name":"University of Regina , , , ,","place":["Regina, Saskatchewan, Canada, S4S 0A2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8378-7480","authenticated-orcid":true,"given":"Tanya E. S.","family":"Dahms","sequence":"additional","affiliation":[{"name":"University of Regina , , , ,","place":["Regina, Saskatchewan, Canada, S4S 0A2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2829-5851","authenticated-orcid":true,"given":"Omar M.","family":"El-Halfawy","sequence":"additional","affiliation":[{"name":"University of Regina , , , ,","place":["Regina, Saskatchewan, Canada, S4S 0A2"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"issue":"3","key":"2026081410080333800_cit1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1097\/MCP.0b013e32835f1afc","article-title":"Respiratory bacterial infections\nin cystic fibrosis","volume":"19","author":"Ciofu","year":"2013","journal-title":"Curr. Opin. Pulm. Med."},{"issue":"12","key":"2026081410080333800_cit2","doi-asserted-by":"publisher","first-page":"3595","DOI":"10.1002\/ppul.25627","article-title":"Review of CFTR modulators 2020","volume":"56","author":"Goetz","year":"2021","journal-title":"Pediatr. Pulmonol."},{"issue":"2","key":"2026081410080333800_cit3","doi-asserted-by":"publisher","first-page":"276","DOI":"10.18553\/jmcp.2021.27.2.276","article-title":"The effectiveness\nand value of novel treatments for\ncystic fibrosis","volume":"27","author":"Tice","year":"2021","journal-title":"J. Manag. Care Spec. Pharm."},{"issue":"1","key":"2026081410080333800_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-022-01431-1","article-title":"CF-Seq, an accessible web application\nfor rapid re-analysis of cystic fibrosis pathogen RNA sequencing studies","volume":"9","author":"Neff","year":"2022","journal-title":"Sci. Data"},{"issue":"6","key":"2026081410080333800_cit5","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1055\/s-0039-1698464","article-title":"Microbiology of Cystic Fibrosis Airway\nDisease","volume":"40","author":"Blanchard","year":"2019","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"2026081410080333800_cit6","volume-title":"2024 Annual Data Report: the Canadian\nCystic Fibrosis Registry","author":"Cystic Fibrosis Canada.","year":"2025"},{"key":"2026081410080333800_cit7","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/s1473-3099(25)00118-5","article-title":"The WHO Bacterial\nPriority Pathogens\nList 2024: a prioritisation study to guide research, development,\nand public health strategies against antimicrobial resistance","volume":"25","author":"Sati","year":"2025","journal-title":"Lancet Infect. Dis."},{"issue":"12","key":"2026081410080333800_cit8","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1002\/ppul.22863","article-title":"Staphylococcus aureus in early cystic\nfibrosis lung disease","volume":"48","author":"Wong","year":"2013","journal-title":"Pediatr. Pulmonol."},{"issue":"23","key":"2026081410080333800_cit9","doi-asserted-by":"publisher","first-page":"2386","DOI":"10.1001\/jama.2010.791","article-title":"Association\nBetween Respiratory Tract Methicillin-Resistant Staphylococcus aureus\nand Survival in Cystic Fibrosis","volume":"303","author":"Dasenbrook","year":"2010","journal-title":"JAMA"},{"issue":"6","key":"2026081410080333800_cit10","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1002\/ppul.20604","article-title":"Presence\nof methicillin resistant Staphylococcus aureus in respiratory cultures\nfrom cystic fibrosis patients is associated with lower lung function","volume":"42","author":"Ren","year":"2007","journal-title":"Pediatr. Pulmonol."},{"key":"2026081410080333800_cit11","volume-title":"Methods for Dilution Antimicrobial\nSusceptibility\nTests for Bacteria That Grow Aerobically; Approved Standard CLSI document\nM07-A9","author":"CLSI.","year":"2012"},{"issue":"1","key":"2026081410080333800_cit12","doi-asserted-by":"publisher","first-page":"330","DOI":"10.3181\/00379727-48-13311","article-title":"A protein-free medium for primary isolation of the\nGonococcus and Meningococcus","volume":"48","author":"Mueller","year":"1941","journal-title":"Proc. Soc. Expt.\nBiol. Med."},{"issue":"4","key":"2026081410080333800_cit13","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.jcf.2012.02.006","article-title":"Results\nof antibiotic susceptibility testing do not influence clinical outcome\nin children with cystic fibrosis","volume":"11","author":"Hurley","year":"2012","journal-title":"J. Cyst Fibros"},{"issue":"5","key":"2026081410080333800_cit14","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1378\/chest.123.5.1495","article-title":"Susceptibility\ntesting of Pseudomonas aeruginosa isolates and clinical response to\nparenteral antibiotic administration: lack of association in cystic\nfibrosis","volume":"123","author":"Smith","year":"2003","journal-title":"Chest"},{"key":"2026081410080333800_cit15","doi-asserted-by":"publisher","first-page":"ii105","DOI":"10.1093\/jac\/dkn357","article-title":"Clinical implications of antimicrobial\nresistance for therapy","volume":"62","author":"Macgowan","year":"2008","journal-title":"J. Antimicrob. 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Med.\nMicrobiol."},{"issue":"4","key":"2026081410080333800_cit18","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1038\/ismej.2014.234","article-title":"A Winogradsky-based culture system shows an association\nbetween microbial fermentation and cystic fibrosis exacerbation","volume":"9","author":"Quinn","year":"2015","journal-title":"ISME J."},{"issue":"13","key":"2026081410080333800_cit19","doi-asserted-by":"publisher","first-page":"4110","DOI":"10.1073\/pnas.1419677112","article-title":"Essential\ngenome of Pseudomonas aeruginosa in cystic fibrosis sputum","volume":"112","author":"Turner","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Antimicrob.\nChemother."},{"issue":"11","key":"2026081410080333800_cit22","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.3390\/microorganisms8111716","article-title":"Colistin update on\nits mechanism of action and resistance, present and future challenges","volume":"8","author":"Andrade","year":"2020","journal-title":"Microorganisms"},{"issue":"1","key":"2026081410080333800_cit23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1023\/a:1016305704057","article-title":"The Molecular Basis for the Mode\nof Action of Beta-Lactam\nAntibiotics and Mechanisms of Resistance","volume":"2","author":"Bycroft","year":"1985","journal-title":"Pharm.\nRes."},{"issue":"1","key":"2026081410080333800_cit24","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3390\/antibiotics9010017","article-title":"More Than a Pore: A\nCurrent Perspective on the In Vivo\nMode of Action of the Lipopeptide Antibiotic Daptomycin","volume":"9","author":"Gray","year":"2020","journal-title":"Antibiotics"},{"issue":"3","key":"2026081410080333800_cit25","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3390\/antibiotics10030263","article-title":"Impact\non Antibiotic Resistance, Therapeutic Success, and Control of Side\nEffects in Therapeutic Drug Monitoring (TDM). of Daptomycin: A Scoping\nReview","volume":"10","author":"Osorio","year":"2021","journal-title":"Antibiotics"},{"issue":"12","key":"2026081410080333800_cit26","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1086\/430352","article-title":"Inhibition\nof Daptomycin by Pulmonary Surfactant: In Vitro Modeling and Clinical\nImpact","volume":"191","author":"Silverman","year":"2005","journal-title":"J. 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Ch."},{"key":"2026081410080333800_cit29","volume-title":"Performance Standards\nfor Antimicrobial Susceptibility Testing CLSI supplement M100","author":"Wayne","year":"2023"},{"issue":"6","key":"2026081410080333800_cit30","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1128\/JCM.02500-06","article-title":"Comparative genomics\nof Canadian epidemic lineages of methicillin-resistant Staphylococcus\naureus","volume":"45","author":"Christianson","year":"2007","journal-title":"J. Clin. Microbiol"},{"issue":"1","key":"2026081410080333800_cit31","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00537-12","article-title":"A genetic\nresource for rapid and\ncomprehensive phenotype screening of nonessential Staphylococcus aureus\ngenes","volume":"4","author":"Fey","year":"2013","journal-title":"mBio"},{"key":"2026081410080333800_cit32","doi-asserted-by":"publisher","first-page":"107652","DOI":"10.1016\/j.ijantimicag.2025.107652","article-title":"Exploring the susceptome of methicillin-resistant\nStaphylococcus aureus to oxacillin and cefazolin using integrated\nTraDIS and proteomics","volume":"66","author":"Abdelmalek","year":"2025","journal-title":"Int. J. Antimicrob. Agents"},{"issue":"5","key":"2026081410080333800_cit33","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1128\/AAC.02070-15","article-title":"Effects\nof low-dose amoxicillin on Staphylococcus aureus USA300 biofilms","volume":"60","author":"Mlynek","year":"2016","journal-title":"Antimicrob. Agents Chemother"},{"issue":"2","key":"2026081410080333800_cit34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/nsmb1047","article-title":"Crystal structure of Staphylococcus\naureus tRNA adenosine deaminase TadA in complex with RNA","volume":"13","author":"Losey","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"issue":"6","key":"2026081410080333800_cit35","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.ijmm.2017.11.011","article-title":"AureoWiki \u0335 The\nrepository\nof the Staphylococcus aureus research and annotation community","volume":"308","author":"Fuchs","year":"2018","journal-title":"Int. J. Med. Microbiol."},{"issue":"34","key":"2026081410080333800_cit36","doi-asserted-by":"publisher","first-page":"12510","DOI":"10.1073\/pnas.1404099111","article-title":"Compound-gene\ninteraction mapping reveals distinct roles for Staphylococcus aureus\nteichoic acids","volume":"111","author":"Santa Maria","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S.\nA."},{"issue":"5","key":"2026081410080333800_cit37","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1128\/JB.187.5.1815-1824.2005","article-title":"Role of penicillin-binding protein 2 (PBP2). in the\nantibiotic susceptibility and cell wall cross-linking of Staphylococcus\naureus: evidence for the cooperative functioning of PBP2, PBP4, and\nPBP2A","volume":"187","author":"\u0141eski","year":"2005","journal-title":"J. Bacteriol."},{"issue":"31","key":"2026081410080333800_cit38","doi-asserted-by":"publisher","first-page":"24055","DOI":"10.1074\/jbc.M110.114793","article-title":"Insertion of epicatechin\ngallate\ninto the cytoplasmic membrane of methicillin-resistant Staphylococcus\naureus disrupts penicillin-binding protein (PBP). 2a-mediated \u03b2-lactam\nresistance by delocalizing PBP2","volume":"285","author":"Bernal","year":"2010","journal-title":"J. Biol. Chem."},{"issue":"12","key":"2026081410080333800_cit39","doi-asserted-by":"publisher","first-page":"5452","DOI":"10.1128\/AAC.00286-11","article-title":"New role of the disulfide stress\neffector YjbH in \u03b2-lactam susceptibility of Staphylococcus aureus","volume":"55","author":"Go\u0308hring","year":"2011","journal-title":"Antimicrob. 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Antimicrob.\nAgents"},{"issue":"2","key":"2026081410080333800_cit49","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1128\/AAC.05054-11","article-title":"GraXSR proteins interact\nwith the VraFG ABC transporter to form a five-component system required\nfor cationic antimicrobial peptide sensing and resistance in Staphylococcus\naureus","volume":"56","author":"Falord","year":"2012","journal-title":"Antimicrob. Agents Chemother"},{"issue":"2","key":"2026081410080333800_cit50","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41589-019-0401-8","article-title":"Discovery of an antivirulence compound that reverses\nbeta-lactam resistance in MRSA","volume":"16","author":"El-Halfawy","year":"2020","journal-title":"Nat. Chem. Biol."},{"issue":"8","key":"2026081410080333800_cit51","doi-asserted-by":"publisher","first-page":"2679","DOI":"10.1128\/AAC.00209-07","article-title":"Interaction of the\nGraRS two-component system with the VraFG ABC transporter to support\nvancomycin-intermediate resistance in Staphylococcus aureus","volume":"51","author":"Meehl","year":"2007","journal-title":"Antimicrob. Agents Chemother"},{"issue":"11","key":"2026081410080333800_cit52","doi-asserted-by":"publisher","first-page":"5658","DOI":"10.1128\/AAC.01184-13","article-title":"Causal role of single\nnucleotide polymorphisms within the mprF gene of Staphylococcus aureus\nin daptomycin resistance","volume":"57","author":"Yang","year":"2013","journal-title":"Antimicrob. Agents\nChemother"},{"key":"2026081410080333800_cit53","doi-asserted-by":"publisher","first-page":"RP87026","DOI":"10.7554\/eLife.87026.3","article-title":"Extensive re-modelling of the cell\nwall during the development of Staphylococcus aureus bacteraemia","volume":"12","author":"Douglas","year":"2023","journal-title":"Elife"},{"issue":"4","key":"2026081410080333800_cit54","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1128\/JB.01201-13","article-title":"Two small\n(p)ppGpp synthases in Staphylococcus aureus mediate tolerance against\ncell envelope stress conditions","volume":"196","author":"Geiger","year":"2014","journal-title":"J. Bacteriol."},{"issue":"10","key":"2026081410080333800_cit55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0213630","article-title":"The Ps\nand Qs of alarmone synthesis in Staphylococcus aureus","volume":"14","author":"Yang","year":"2019","journal-title":"PLoS One"},{"issue":"3","key":"2026081410080333800_cit56","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1089\/mdr.2013.0053","article-title":"Whole-genome\nsequencing reveals a link between \u03b2-lactam resistance and synthetases\nof the alarmone (p). ppGpp in Staphylococcus aureus","volume":"19","author":"Mwangi","year":"2013","journal-title":"Microb. Drug Resist."},{"issue":"3","key":"2026081410080333800_cit57","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1021\/ja0759139","article-title":"Selective Fluorescent\nChemosensor for the Bacterial Alarmone (p)ppGpp","volume":"130","author":"Rhee","year":"2008","journal-title":"J. Am. Chem. 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