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dc.contributor.authorBartlett, Sean
dc.date.accessioned2017-12-13T10:28:50Z
dc.date.available2017-12-13T10:28:50Z
dc.date.issued2017-11-01
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/270198
dc.description.abstractHospital-acquired infections are the most frequent adverse event in healthcare delivery worldwide. Seven in ten hospital-acquired infections exhibit resistance to at least one antibiotic, and three in five doctors have encountered an infection unresponsive to any treatment at all. This prolongs hospitalisation, increases suffering, and causes long-term disability and unnecessary death. At present the antibiotic pipeline is unable to meet the demand for novel antibiotics needed to treat these infections. Herein I discuss how the lack of new scaffolds, limitations of target-based screening, and poor target validation each contribute to the current bottleneck in the antibiotic pipeline. In turn, I argue that the development and application of chemical probes is a more fruitful way to make progress towards new antibiotics with novel mechanisms of action. This dissertation describes a combined chemical-biology study in the search for novel inhibitors of the human pathogens Pseudomonas aeruginosa and Staphylococcus aureus. First we extend organocatalysis to the field of diversity-oriented synthesis as a powerful means to generate molecular diversity and complexity in small molecule screening collections. We then study a family of potential biofilm inhibitors identified from a diverse screening collection, and for which we suggest a possible mode of action upon the quorum sensing receptors LasR and RhlR. Thereafter we provide evidence that a novel macrocycle, based upon the cylindrocyclophane family of natural products, inhibits methicillin-resistant S. aureus through action upon the respiratory chain. Finally, we also report insights into the structure and small molecule inhibition of a key P. aeruginosa drug target, malate synthase G. Together the findings in this dissertation encourage the development and application of divergent synthesis and unbiased screening methods in antibacterial discovery.
dc.description.sponsorshipHerchel Smith Fund
dc.language.isoen
dc.rightsNo Creative Commons licence (All rights reserved)
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectantibiotics
dc.subjectdrug resistance
dc.subjectsynthesis
dc.titleSynthesis and antibacterial evaluation of diverse small molecules
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentDepartment of Chemistry
dc.date.updated2017-12-12T16:52:44Z
dc.identifier.doi10.17863/CAM.17036
dc.contributor.orcidBartlett, Sean [0000-0002-7044-4454]
dc.publisher.collegeCorpus Christi College
dc.type.qualificationtitlePhD in Chemistry
cam.supervisorSpring, David R.
rioxxterms.freetoread.startdate2400-01-01


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