{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:31:20Z","timestamp":1785429080192,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jadara University, Jordan","award":["2018551"],"award-info":[{"award-number":["2018551"]}]},{"award":["2018551"],"award-info":[{"award-number":["2018551"]}],"id":[{"id":"https:\/\/ror.org\/001drnv35","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Innovate UK and the UK Department of Health and Social Care (DHSC) through an SBRI","award":["106368\u2013623146"],"award-info":[{"award-number":["106368\u2013623146"]}]},{"award":["106368\u2013623146"],"award-info":[{"award-number":["106368\u2013623146"]}],"id":[{"id":"https:\/\/ror.org\/03sbpja79","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"crossref","award":["CF-2021-2\/102"],"award-info":[{"award-number":["CF-2021-2\/102"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CF-2021-2\/102"],"award-info":[{"award-number":["CF-2021-2\/102"]}],"id":[{"id":"https:\/\/ror.org\/04e3zg361","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Research Foundation under its Open Fund Individual Research","award":["MOH-000963"],"award-info":[{"award-number":["MOH-000963"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Teixobactin is a promising antibiotic that targets cell wall biosynthesis in Gram-positive bacteria and displays a low propensity for resistance; however, its structural complexity presents challenges for analogue development and optimisation. In this study, we investigated the effects of macrocycle size and replacement of the native depsipeptide linkage with an amide bond on antibacterial activity using a simplified Leu10-teixobactin scaffold. An amide-based macrocyclisation strategy was developed for efficient lactam formation using readily accessible amino acid building blocks, avoiding reliance on synthetically demanding modified diamino acids employed in other approaches. Two complementary synthetic routes provided access to a series of ten analogues, comprising linear and macrocyclised variants with systematic variation at position 8. Antibacterial activity was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant clinical isolates. While linear analogues exhibited weak or no measurable antibacterial activity, macrocyclised analogues retained measurable antibacterial activity, indicating that macrocyclisation is essential within this scaffold, whereas moderate expansion of the macrocycle was tolerated. The structure\u2013activity relationships identified here demonstrate the suitability of a simplified Leu10-teixobactin framework and provide a platform for further optimisation of teixobactin-inspired antibiotics.<\/jats:p>","DOI":"10.3390\/biom16070970","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:41:38Z","timestamp":1782909698000},"page":"970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Understanding the Role of Macrocycle Size and Amide Linkage in Teixobactin Analogues"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9025-6752","authenticated-orcid":false,"given":"Ruba","family":"Malkawi","sequence":"first","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"},{"name":"School of Pharmacy, Jadara University, P.O. Box 733, Irbid 21110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Weldon-Bee","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2459-7224","authenticated-orcid":false,"given":"Edwin","family":"Kiptoo","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjit","family":"Das","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinzhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"},{"name":"Department of Chemistry and Materials Science, Xi\u2019an-Jiaotong Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Iyer","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Lincoln, JBL Building, Beevor St., Lincoln LN6 7DL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8214-5315","authenticated-orcid":false,"given":"Rajamani","family":"Lakshminarayanan","sequence":"additional","affiliation":[{"name":"Singapore Eye Research Institute, Singapore 169857, Singapore"},{"name":"Department of Pharmacy & Pharmaceutical Sciences, National University of Singapore, Singapore 117543, Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Chemistry and Materials Science, Xi\u2019an-Jiaotong Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Parmar","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7822-1063","authenticated-orcid":false,"given":"Ishwar","family":"Singh","sequence":"additional","affiliation":[{"name":"Antimicrobial Drug Discovery and Development, The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, William Henry Duncan Building, 6 West Derby St., Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e0199121","DOI":"10.1128\/aac.01991-21","article-title":"Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is 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