@phdthesis{Diwischek2008,
  author    = {Diwischek, Florian},
  title     = {Development of synthesis pathways and characterization of cerulenin analogues as inhibitors of the fatty acid biosynthesis of Mycobacterium tuberculosis and of efflux pump resistant Candida albicans},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27532},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {The work deals with the synthesis and characterization of cerulenin analogues as inhibitors of efflux pump mediated resistance of Candida albicans isolates and as inhibitors of the fatty acid synthesis enzyme KasA of Mycobacterium tuberculosis. Cerulenin was chosen as the lead structure, being a substrate of the efflux pumps in Candida albicans on one hand and therefore variations on the structure could lead to a blocking of the efflux pumps as in the case of tetracycline and inhibitor 13-CPTC of the TetB efflux pump. On the other hand, cerulenin is a known inhibitor of the FAS system but inhibition is unselective in type I and II FAS. Therefore, analogues could result in increased selectivity towards the type II FAS system in M. tuberculosis. The first cerulenin derivatives were prepared by coupling 2,3-dihydrofuran to the before synthesized 1-octaniodide, followed by ring opening and oxidation in one step by chromic acid and transfer of the resulting 4-keto acid to amides to give analogues 4a-d, 4e was prepared in analogy. To include the epoxide function especially with regard to the mechanism of action of cerulenin in the FAS system (considering known crystal structures of cerulenin and the KasA analogue of E. coli) tetrahydro- and dihydrocerulenin analogues were synthesized. Starting from the corresponding aldehyde, lactone 5 (tetrahydrocerulenin analogues) was obtained via two different routes A and B. Route A included the coupling of the aldehyde 1-nonanal to propiolic acid via a Grignard reaction with subsequent hydrogenation with the Lindlar catalyst under hydrogen pressure to give 5. Via Route B 1-nonanal was coupled to methyl propiolate by n-BuLi with subsequent hydrogenation under reflux with the catalytic system Lindlar cat./NH4HCO2 to yield 5. These hydrogenations were also executed in a microwave oven resulting in better yields and/or reaction times. The lactone 5 was then epoxidized, the ring opened by amidation and the remaining alcohol was oxidized via Collins oxidation to result in tetrahydrocerulenin analogues 8a-e. The same procedure was used for dihydrocerulenin analogues 10a-c except that to obtain the corresponding lactone 9a only route A was used and a further step had to be executed for ring closure. To obtain analogues with all structural features of cerulenin including two double bonds and the epoxide function, a third pathway was chosen. To obtain the future side chain, aldehyde 12 was synthesized by coupling protected 4-pentyn-1-ol to either crotyl bromide or crotyl chloride, which then was deprotected, hydrogenated with Lindlar catalyst under hydrogen pressure and oxidized via a Swern oxidation. The following synthesis sequence starting from 12 was executed similar to that of dihydrocerulenins via the corresponding lactone (51) with the major exception of the oxidation procedure in the last step via TPAP/NMO to result in (4Z,7E)-cerulenin analogues 15a-b. A fourth class of cerulenin analogues was synthesized with the aromatic analogues 17a-e. This synthesis pathway started with the formation of the benzoyl acrylamides 16a-e from benzoylacrylic acid via a mixed anhydride which was prepared with isobutylchloroformate followed by the addition of the corresponding amine. Subsequent epoxidation with H2O2 in basic EtOH gave the aromatic cerulenin analogues 17a-e. Pharmacological testings for the synthesized substances were executed on efflux pump-resistant and -sensitive Candida albicans isolates, on the fatty acid synthesis enzyme KasA of Mycobacterium tuberculosis and on other organisms such as Leishmania major, Trypanosoma brucei brucei, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa within the Sonderforschungsbereich 630.},
  subject      = {Organische Synthese},
  language  = {en}
}
@phdthesis{Loeff2021,
  author    = {Loeff, Rebekka Magdalena},
  title     = {Screening auf multiresistente Erreger, Erhebung von Tuberkulose- und Impfstatus sowie sonstiger meldepflichtiger Infektionskrankheiten bei Gefl{\"u}chteten am Universit{\"a}tsklinikum W{\"u}rzburg im Zeitraum vom 1.11.2015 bis 30.04.2016},
  doi       = {10.25972/OPUS-23942},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239424},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Hintergrund: Gefl{\"u}chtete haben ein hohes Risiko, Multiresistente Erreger (MRE) zu tragen. Infektionen mit MRE (Multiresistente Gram-negative Bakterien [MRGN] und Methicillin-resistenter Staphylococcus aureus [MRSA]) sind mit einer erh{\"o}hten Mortalit{\"a}t, Krankenhausaufenthaltsdauer und Krankenhauskosten assoziiert. Der Einfluss von pr{\"a}disponierenden Faktoren f{\"u}r eine Besiedlung mit MRE ist f{\"u}r Gefl{\"u}chtete noch unzureichend erforscht. Kenntnisse {\"u}ber pr{\"a}disponierende Faktoren k{\"o}nnen helfen, Infektionsschutzmaßnahmen f{\"u}r Gefl{\"u}chtete in Krankenh{\"a}usern anzupassen. Methodik: Von November 2015 bis April 2016 wurden 134 Gefl{\"u}chtete am Universit{\"a}tsklinikum W{\"u}rzburg auf MRE im Nasen-/Rachen- (MRSA), Rektal- (MDRGN-Enterobacteriaceae, MDRGN-Pseudomonas aeruginosa) und Haut-/Rachenabstrich (MDRGN-Acinetobacter baumannii) gescreent. Ergebnisse: 62,7\% von 134 gescreenten Fl{\"u}chtlingen waren m{\"a}nnlichen Geschlechts und das Durchschnittsalter lag bei 19 Jahren [IQR: 7-31]. 23,9\% (n=32) zeigten einen positiven MRE-Befund (MRSA: 3,4 \% von 118, 2MDRGN-Neop{\"a}d: 19,3 \% von 57, 3MDRGN: 13,6 \% von 125, 4MDRGN: 0 \% von 125). Es wurden 25 Escherichia coli (98,3\%), 3 Klebsiella pneumoniae (10,7\%) und keine positiven Befunde auf Pseudomonas aeruginosa oder Acinetobacter baumannii gefunden. 3 Gefl{\"u}chtete (9,6\%) zeigten eine Mehrfachbesiedlung und 2 Gefl{\"u}chtete (6,2\%) wiesen eine durch MRE bedingte Infektionserkrankung auf (submandibul{\"a}rer Abszess, Pyelonephritis). Bei 94 Gefl{\"u}chteten mit vollst{\"a}ndigem Screening waren Gefl{\"u}chtete mit positivem MRE-Befund im Vergleich zu Gefl{\"u}chteten mit negativem MRE-Befund j{\"u}ngeren Alters (Medianalter: 8 Jahre [IQR: 3-36] vs. 24 Jahre [IQR: 14-33]) und vermehrt weiblichen Geschlechts (61,1\%). Gefl{\"u}chtete mit positivem MRE-Befund wiesen zudem im Vergleich vermehrt pr{\"a}disponierende Faktoren auf, bspw. einen vorherigen Krankenhausaufenthalt (61,1 \% vs. 35,5\%), chronische Pflegebed{\"u}rftigkeit (16,7 \% vs. 1,3 \%) oder eine Fluchtanamnese ≤ 3 Monate (80,0 \% vs. 29,4 \%). Schlussfolgerung: Pr{\"a}disponierende Faktoren spielen eine große Rolle f{\"u}r eine Besiedlung mit MRE. Prospektive Studien sollten folgen, um pr{\"a}disponierende Faktoren f{\"u}r eine Besiedlung mit MRE bei Gefl{\"u}chteten besser charakterisieren zu k{\"o}nnen.},
  subject      = {Gefl{\"u}chtete},
  language  = {de}
}
@phdthesis{Luckner2009,
  author    = {Luckner, Sylvia},
  title     = {Towards the development of high affinity InhA and KasA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-43621},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {Mycobacterium tuberculosis is the causative agent of tuberculosis and responsible for more than eight million new infections and about two million deaths each year. Novel chemotherapeutics are urgently needed to treat the emerging threat of multi drug resistant and extensively drug resistant strains. Cell wall biosynthesis is a widely used target for chemotherapeutic intervention in bacterial infections. In mycobacteria, the cell wall is comprised of mycolic acids, very long chain fatty acids that provide protection and allow the bacteria to persist in the human macrophage. The type II fatty acid biosynthesis pathway in Mycobacterium tuberculosis synthesizes fatty acids with a length of up to 56 carbon atoms that are the precursors of the critical mycobacterial cell wall components mycolic acids. KasA, the mycobacterial ß-ketoacyl synthase and InhA, the mycobacterial enoyl reductase, are essential enzymes in the fatty acid biosynthesis pathway and validated drug targets. In this work, KasA was expressed in Mycobacterium smegmatis, purified and co-crystallized in complex with the natural thiolactone antibiotic thiolactomycin (TLM). High-resolution crystal structures of KasA and the C171Q KasA variant, which mimics the acyl enzyme intermediate of the enzyme, were solved in absence and presence of bound TLM. The crystal structures reveal how the inhibitor is coordinated by the enzyme and thus specifically pinpoint towards possible modifications to increase the affinity of the compound and develop potent new drugs against tuberculosis. Comparisons between the TLM bound crystal structures explain the preferential binding of TLM to the acylated form of KasA. Furthermore, long polyethylene glycol molecules are bound to KasA that mimic a fatty acid substrate of approximately 40 carbon atoms length. These structures thus provide the first insights into the molecular mechanism of substrate recognition and reveal how a wax-like substance can be accommodated in a cytosolic environment. InhA was purified and co-crystallized in complex with the slow, tight binding inhibitor 2-(o-tolyloxy)-5-hexylphenol (PT70). Two crystal structures of the ternary InhA-NAD+-PT70 were solved and reveal how the inhibitor is bound to the substrate binding pocket. Both structures display an ordered substrate binding loop and corroborate the hypothesis that slow onset inhibition is coupled to loop ordering. Upon loop ordering, the active site entrance is more restricted and the inhibitor is kept inside more tightly. These studies provide additional information on the mechanistic imperatives for slow onset inhibition of enoyl ACP reductases.},
  subject      = {Tuberkelbakterium},
  language  = {en}
}