Vis enkel innførsel

dc.contributor.advisorBayer, Annette
dc.contributor.authorKondratieva, Alexandra
dc.date.accessioned2024-06-06T09:20:12Z
dc.date.available2024-06-06T09:20:12Z
dc.date.issued2024-06-26
dc.description.abstract<p>Antimicrobial resistance (AMR) achieved through, among others, β-lactamase activity, remains an ongoing challenge for the treatment of infections caused by antibiotic-resistant pathogens. Metallo-β-lactamase (MBL)-expressing bacteria, resistant to most β-lactam antibiotics, are of growing clinical relevance with currently no approved treatment options available. The most common approaches to combating AMR include the modification of existing compounds or the development of new drugs and inhibitors. Alternative strategies are also being explored, including novel drug delivery systems. Recently, an approach based on exploiting the ability of MBLs to hydrolyze β-lactams has been investigated using cephalosporin prodrugs. The reported conjugates consisted of aromatic thiol-based MBL inhibitors linked to a cephalosporin scaffold that was designed to release the inhibitors upon enzymatic hydrolysis. <p>The goal of the current work was to extend the concept of thiol-releasing conjugates to aliphatic thiolbased MBL inhibitors, as aliphatic thiols have been described to lack the required leaving group properties. The work is based on the hypothesis that fluorination in the vicinity of the thiol moiety can be used as a tool in the design of aliphatic thiol-releasing conjugates. <p>Thus, the initial focus was on designing fluorinated captopril analogues, exhibiting inhibitory activity against relevant MBLs, and investigating the influence of fluorination on their inhibitory effect. A library of fluorinated thiols, of which several exhibited IC<sub>50</sub> values in the low micromolar region against NDM-1, was developed. Furthermore, the use of fluorinated inhibitors as probes for NMR-based binding studies was demonstrated on a representative compound. <p>Among the active thiols, a few were selected for attachment to the cephalosporin core, resulting in a series of conjugates. The hydrolysis of the conjugates was examined and the inhibitory activity against several MBLs was determined. The conjugates were shown to release the thiols, as determined by LCMS and NMR. In addition, IC<sub>50</sub> values of the conjugates were found to be in a similar range to the respective thiol inhibitors. <p>In summary, the obtained conjugates verified that fluorination facilitates the release of aliphatic thiolbased inhibitors and provide directions for future conjugate development. Moreover, fluorinated thiol inhibitors can assist in studies of inhibitor-enzyme interactions and conjugate hydrolysis utilizing <sup>19</sup>F NMR methods.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractAntibiotic-resistant pathogens present a threat to global health as the available treatment options are not always effective. A well-recognized approach is the use of inhibitors that can counteract a bacterial resistance mechanism, thus re-activating the antibiotic effect. A recent approach in inhibitor development is the design of prodrugs that release an active molecule, the inhibitor, only in the presence of resistant bacteria. Extending this approach to inhibitors previously reported as having problems with release was the focus of this work. We hypothesized that introduction of fluorine atoms into the molecular structure of the inhibitors would facilitate release. The obtained compounds were shown to release the biologically active moieties as determined by spectroscopic assays. Furthermore, the compounds were found to be a useful tool for analyzing biochemical interactions. These findings can provide insights for the design and studies of the next generation of prodrugs.en_US
dc.identifier.isbn978-82-8236-578-9 - Trykk
dc.identifier.isbn978-82-8236-579-6 - pdf
dc.identifier.urihttps://hdl.handle.net/10037/33756
dc.language.isoengen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.relation.haspart<p>Paper I: Alexandra Kondratieva, Katarzyna Palica, Christopher Frøhlich, Rebekka Rolfsnes Hovd, Hanna-Kirsti S. Leiros, Mate Erdelyi, Annette Bayer (2024). Fluorinated Captopril Analogues Inhibit Metallo-β-Lactamases and Facilitate Structure Determination of NDM-1 Binding Pose. <i>European Journal of Medicinal Chemistry, 266</i>, 116140. Also available in Munin at <a href=https://hdl.handle.net/10037/32797>https://hdl.handle.net/10037/32797</a>. <p>Paper II: Alexandra Kondratieva, Philip Rainsford, Perwez Bakht, Hanna-Kirsti S. Leiros, Ranjana Pathania, Annette Bayer. The Use of Fluorinated Aliphatic Thiols in the Design of Cephalosporin Conjugates. (Manuscript).en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2024 The Author(s)
dc.subject.courseIDDOKTOR-004
dc.subjectThiolsen_US
dc.subjectInhibitorsen_US
dc.subjectMetallo-β-lactamasesen_US
dc.subjectConjugatesen_US
dc.titleExploring fluorination in MBL inhibitor designen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


Tilhørende fil(er)

Thumbnail
Thumbnail

Denne innførselen finnes i følgende samling(er)

Vis enkel innførsel