{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:28:11Z","timestamp":1790364491345,"version":"4.1.0"},"reference-count":50,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T00:00:00Z","timestamp":1599523200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-156214"],"award-info":[{"award-number":["PJT-156214"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012171","name":"Ontario Research Foundation","doi-asserted-by":"publisher","award":["ORF-RE09-047"],"award-info":[{"award-number":["ORF-RE09-047"]}],"id":[{"id":"10.13039\/100012171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The growing challenge of microbial resistance emphasizes the importance of new antibiotics or reviving strategies for the use of old ones. Macrolide antibiotics are potent bacterial protein synthesis inhibitors with a formidable capacity to treat life-threatening bacterial infections; however, acquired and intrinsic resistance limits their clinical application. In the work presented here, we reveal that bicarbonate is a potent enhancer of the activity of macrolide antibiotics that overcomes both acquired and intrinsic resistance mechanisms. With a focus on azithromycin, a highly prescribed macrolide antibiotic, and using clinically relevant pathogens, we show that physiological concentrations of bicarbonate overcome drug resistance by increasing the intracellular concentration of azithromycin. We demonstrate the potential of bicarbonate as a formulation additive for topical use of azithromycin in treating a murine wound infection caused by Pseudomonas aeruginosa. Further, using a systemic murine model of methicillin-resistant Staphylococcus aureus (MRSA) infection, we demonstrate the potential role of physiological bicarbonate, naturally abundant in the host, to enhance the activity of azithromycin against macrolide-resistant MRSA. In all, our findings suggest that macrolide resistance, observed in the clinical microbiology laboratory using standard culturing techniques, is a poor predictor of efficacy in the clinic and that observed resistance should not necessarily hamper the use of macrolides. Whether as a formulation additive for topical use or as a natural component of host tissues, bicarbonate is a powerful potentiator of macrolides with the capacity to overcome drug resistance in life-threatening bacterial infections.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00340","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T18:48:34Z","timestamp":1599590914000},"page":"2709-2718","source":"Crossref","is-referenced-by-count":37,"title":["Overcoming Acquired and Native Macrolide Resistance\nwith Bicarbonate"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-7377","authenticated-orcid":true,"given":"Maya A.","family":"Farha","sequence":"first","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"MacNair","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Carfrae","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0039-1780","authenticated-orcid":true,"given":"Sara S.","family":"El Zahed","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4993-9823","authenticated-orcid":true,"given":"Michael J.","family":"Ellis","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiu-Ki R.","family":"Tran","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"McArthur","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-8112","authenticated-orcid":true,"given":"Eric D.","family":"Brown","sequence":"additional","affiliation":[{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]},{"name":"McMaster University , , , ,","place":["Hamilton, Ontario, Canada, L8N 3Z5"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,9,8]]},"reference":[{"key":"2026081722113953800_cit1","doi-asserted-by":"publisher","first-page":"S122","DOI":"10.1038\/nm1145","article-title":"Antibacterial\nresistance worldwide: causes, challenges\nand responses","volume":"10","author":"Levy","year":"2004","journal-title":"Nat. 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Sci."},{"key":"2026081722113953800_cit5","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1086\/324626","article-title":"Mechanisms\nof resistance to macrolides and lincosamides: nature of the resistance\nelements and their clinical implications","volume":"34","author":"Leclercq","year":"2002","journal-title":"Clin.\nInfect. Dis."},{"key":"2026081722113953800_cit6","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1056\/NEJMc1212055","article-title":"U.S. outpatient\nantibiotic prescribing, 2010","volume":"368","author":"Hicks","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"2026081722113953800_cit7","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1017\/ice.2018.26","article-title":"Outpatient Antibiotic Prescription\nTrends in the United States: A National Cohort Study","volume":"39","author":"Durkin","year":"2018","journal-title":"Infect Control Hosp Epidemiol"},{"key":"2026081722113953800_cit8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/antibiotics5030029","article-title":"From Erythromycin\nto Azithromycin and New Potential\nRibosome-Binding Antimicrobials","volume":"5","author":"Jelic","year":"2016","journal-title":"Antibiotics\n(Basel, Switz.)"},{"key":"2026081722113953800_cit9","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1128\/MMBR.00016-10","article-title":"Origins and evolution\nof antibiotic resistance","volume":"74","author":"Davies","year":"2010","journal-title":"Microbiol. Mol. 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Clin\nDiagn Res."},{"key":"2026081722113953800_cit31","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.1128\/AAC.46.9.2727-2734.2002","article-title":"Resistance to macrolides and related antibiotics in\nStreptococcus pneumoniae","volume":"46","author":"Leclercq","year":"2002","journal-title":"Antimicrob. Agents\nChemother."},{"key":"2026081722113953800_cit32","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1093\/jac\/43.4.559","article-title":"Inducible or constitutive expression\nof resistance in clinical isolates of streptococci and enterococci\ncross-resistant to erythromycin and lincomycin","volume":"43","author":"Rosato","year":"1999","journal-title":"J. Antimicrob. 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Med."},{"key":"2026081722113953800_cit36","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s13205-013-0133-5","article-title":"Incidence of constitutive\nand inducible clindamycin resistance among\nhospital-associated Staphylococcus aureus","volume":"4","author":"Sasirekha","year":"2014","journal-title":"3\nBiotech"},{"key":"2026081722113953800_cit37","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1128\/JCM.00960-11","article-title":"Evaluation\nof disk approximation and single-well broth tests for detection of\ninducible clindamycin resistance in Streptococcus pneumoniae","volume":"49","author":"Jorgensen","year":"2011","journal-title":"J. Clin. 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Antimicrob.\nChemother."},{"key":"2026081722113953800_cit40","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1378\/chest.123.3.772","article-title":"Efficacy and safety\nof azithromycin vs levofloxacin in the outpatient treatment of acute\nbacterial exacerbations of chronic bronchitis","volume":"123","author":"Amsden","year":"2003","journal-title":"Chest"},{"key":"2026081722113953800_cit41","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1164\/rccm.201502-0212OC","article-title":"The Effect\nof Macrolide Resistance on the Presentation and Outcome of Patients\nHospitalized for Streptococcus pneumoniae Pneumonia","volume":"191","author":"Cilloniz","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2026081722113953800_cit42","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1164\/rccm.201504-0701ED","article-title":"Macrolide-Resistant\nPneumococcus in Community-acquired Pneumonia. Is There Still a Role\nfor Macrolide Therapy?","volume":"191","author":"Niederman","year":"2015","journal-title":"Am. J. Respir. Crit.\nCare Med."},{"key":"2026081722113953800_cit43","doi-asserted-by":"publisher","first-page":"2835","DOI":"10.1093\/jac\/dku207","article-title":"Clinical cure rates in subjects treated\nwith azithromycin for community-acquired respiratory tract infections\ncaused by azithromycin-susceptible or azithromycin-resistant Streptococcus\npneumoniae: analysis of Phase 3 clinical trial data","volume":"69","author":"Zhanel","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"2026081722113953800_cit44","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1093\/jac\/dkr040","article-title":"Effectiveness and safety of macrolides\nin cystic fibrosis patients:\na meta-analysis and systematic review","volume":"66","author":"Cai","year":"2011","journal-title":"J. Antimicrob.\nChemother."},{"key":"2026081722113953800_cit45","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1001\/jama.290.13.1749","article-title":"Azithromycin in patients with cystic\nfibrosis chronically infected with Pseudomonas aeruginosa: a randomized\ncontrolled trial","volume":"290","author":"Saiman","year":"2003","journal-title":"JAMA"},{"issue":"B","key":"2026081722113953800_cit46","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/jac\/41.suppl_2.37","article-title":"Anti-inflammatory\nactivity of macrolides: a new therapeutic potential?","volume":"41","author":"Labro","year":"1998","journal-title":"J. Antimicrob. Chemother."},{"key":"2026081722113953800_cit47","doi-asserted-by":"publisher","first-page":"331","DOI":"10.2147\/COPD.S681","article-title":"Role of macrolide\ntherapy in chronic\nobstructive pulmonary disease","volume":"3","author":"Martinez","year":"2008","journal-title":"Int. J. Chronic\nObstruct. Pulm. Dis."},{"key":"2026081722113953800_cit48","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.prrv.2009.12.003","article-title":"The role of azithromycin in patients with cystic fibrosis","volume":"11","author":"Yousef","year":"2010","journal-title":"Paediatr Respir Rev."},{"key":"2026081722113953800_cit49","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1128\/AAC.50.5.1680-1688.2006","article-title":"Quorum-sensing antagonistic\nactivities of azithromycin\nin Pseudomonas aeruginosa PAO1: a global approach","volume":"50","author":"Nalca","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081722113953800_cit50","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/nchembio.559","article-title":"Combinations\nof antibiotics and nonantibiotic drugs enhance antimicrobial efficacy","volume":"7","author":"Ejim","year":"2011","journal-title":"Nat. Chem. Biol."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.0c00340","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/10\/2709\/6313147\/id0c00340.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/10\/2709\/6313147\/id0c00340.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:35:21Z","timestamp":1787042121000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/10\/2709\/614091\/Overcoming-Acquired-and-Native-Macrolide"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,8]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,9,8]]},"published-print":{"date-parts":[[2020,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.0c00340","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,8]]}}}