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Title: Design, synthesis and evaluation of novel compounds as the NDM-1 inhibitors to fight antibiotic resistance
Authors: Jin, Wen Bin
Degree: Ph.D.
Issue Date: 2018
Abstract: The rapid development and increasing rate of antibiotic resistance among bacterial pathogens have threatened to take human back to the "post-antibiotic era". The metallo-β-lactamase, NDM-1, hydrolyzes nearly all β-lactam antibiotics including carbapenems, which were considered as "drugs of last resort". Limited advance has been achieved due to the lack of efficient countermeasures for treating infections by bacterial strain carrying blaNDM-1 gene and the clinical inhibitors against NDM-1 are still lacking up to date. After all, discovery of novel NDM-1 inhibitors is a challenging but rewarding research area. Here my thesis reports three different classes of compounds that target NDM-1. In the first part of my studies, a series of pyrrolidine derivatives serving as NDM-1 inhibitors have been designed and synthesized based on the scaffold of a well-known NDM-1 inhibitor, L-captopril. The SAR study of thirty six compounds suggests that modification at the N atom enjoyed the priority. Especially, the compound Chen45 with a bis(pyridine-2-ylmethyl)amino substituent displayed the most potent inhibitory activity against NDM-1 and restored the antibacterial activity of MRM against Escherichia coli BL21 carrying NDM-1 plasmid with RF value of 256. Screening of several clinical isolated strains carrying various MBLs including NDM-1 enzyme suggests that compound Chen45 exhibited the activity of attenuating the antibiotic resistance toward MRM. Nano ESI-MS analysis confirmed the inactivation mechanism that compound Chen45 can remove two zinc ions from NDM-1, which is similar to the inhibition mechanism of AMA.
In the second part of my studies, a total of 47 ebselen analogues were designed, synthesized and evaluated for their NDM-1 inhibiting activity in Escherichia coli TG1 carrying NDM-1 and the activity of attenuating the antibiotic resistance in clinical isolated strains Enterobacter cloacae. The SAR study revealed two crucial functional groups including that addition of chlorine on the phenyl ring and N-Boc protected amine with a long chain. The mechanism illustrated the ability to form covalent bonds with thiol groups of cysteine residue in NDM-1. More importantly, compound Qi43, a more promising candidate for future NDM-1 inhibitor development than ebselen, has been proved to be very low toxicity to animal cells and have stronger synergistic effect with meropenem on clinical isolated strains. In the third part of my studies, a series of isothiazol-3-one derivatives have been designed and synthesized. Most of them displayed potent inhibition activity against the NDM-1 carrying E.coli. SAR study suggests that the rigid N-phenyl ring linker with halogen substituent would be preferable. Compound ISO-1, showed the most potent activity. At 2 μg/mL, it showed 128-fold MIC reduction of MRM, which is better than the control compound ebselen. The IC50 is about 0.44 ± 0.02 μM, which is comparable with AMA. ESI-MS results also indicated that it could covalently bind to the enzyme by forming the S-S bond with the cysteine residue of the NDM-1 enzyme.
Subjects: Hong Kong Polytechnic University -- Dissertations
Drug resistance
Pages: xi, 323 pages : color illustrations
Appears in Collections:Thesis

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