{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:03:33Z","timestamp":1753877013311,"version":"3.41.2"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T00:00:00Z","timestamp":1728691200000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP1153493"],"award-info":[{"award-number":["APP1153493"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilized in TB treatment to date.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Based on inhibitory concentration, oral bioavailability, and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, and flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin, and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The order of activity of beta-lactams was cefadroxil\u00a0&amp;gt;\u00a0tebipenem\u00a0&amp;gt;\u00a0cephradine\u00a0&amp;gt;\u00a0cephalexin\u00a0&amp;gt;\u00a0cefdinir\u00a0&amp;gt;\u00a0penicillin V\u00a0&amp;gt;\u00a0flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir\/cephradine, cefadroxil\/tebipenem, cefadroxil\/penicillin V, cefadroxil\/cefdinir, cephalexin\/tebipenem, cephalexin\/penicillin V, cephalexin\/cefdinir, cephalexin\/cephradine, and cefadroxil\/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin, or linezolid resulted in antagonistic effects, except for the combinations of penicillin V\/levofloxacin, penicillin V\/moxifloxacin, and cefdinir\/moxifloxacin.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Beta-lactam synergy may provide viable combination therapies for the treatment of TB.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jambio\/lxae255","type":"journal-article","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T04:16:23Z","timestamp":1728706583000},"source":"Crossref","is-referenced-by-count":0,"title":["Synergistic oral beta-lactam combinations for treating tuberculosis"],"prefix":"10.1093","volume":"135","author":[{"given":"Diana H","family":"Quan","sequence":"first","affiliation":[{"name":"Tuberculosis Research Program, Centenary Institute, The University of Sydney , 2006 NSW ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trixie","family":"Wang","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Program, Centenary Institute, The University of Sydney , 2006 NSW ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Martinez","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases and Microbiology, The Westmead Institute , 2145 NSW ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah Y","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Sydney , 2006 NSW ,","place":["Australia"]},{"name":"Sydney Infectious Diseases Institute, Faculty of Medicine and Health, The University of Sydney , Camperdown, 2006 NSW 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