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However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to \u03b2\u2010lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with \u03b2\u2010lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all\u2010carbon ring, the amide N is substituted by a tertiary C\u2212H \u03b1 to a ketone. Cyclobutanone analogues of various \u03b2\u2010lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the \u03b2\u2010lactamase enzymes that impart resistance to \u03b2\u2010lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of \u03b2\u2010lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of \u03b2\u2010lactamase; other compounds from this family inhibit <jats:italic>Streptomyces<\/jats:italic> R61 <jats:sc>dd<\/jats:sc>\u2010carboxypeptidase\/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.<\/jats:p>","DOI":"10.1002\/cbic.201600529","type":"journal-article","created":{"date-parts":[[2016,12,19]],"date-time":"2016-12-19T09:22:41Z","timestamp":1482139361000},"page":"338-351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Cyclobutanone Analogues of \u03b2\u2010Lactam Antibiotics: \u03b2\u2010Lactamase Inhibitors with Untapped Potential?"],"prefix":"10.1002","volume":"18","author":[{"given":"Prarthana","family":"Devi","sequence":"first","affiliation":[{"name":"School of Chemistry The University of Sydney  Sydney NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0767-5196","authenticated-orcid":false,"given":"Peter J.","family":"Rutledge","sequence":"additional","affiliation":[{"name":"School of Chemistry The University of Sydney  Sydney NSW 2006 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,2,7]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"J. 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