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Title: Structure-activity relationship (SAR) of some isatin-based glycosyltransferase inhibitors : molecular design, synthesis and antibacterial activities
Authors: Cheong, Wing Lam
Degree: Ph.D.
Issue Date: 2018
Abstract: Antibacterial Resistance (ABR) has been a global challenge. The abusive use of antibiotics stimulates natural selection of bacteria and results in loss of activity against their targets. Peptidoglycan glycosyltransferase (GT), an enzyme which is essential for cell wall biosynthesis, is a potential novel drug target. It offers several advantages as a drug target: (i) it is absent in human cells; (ii) its sequence is highly conserved among bacteria; (iii) it is easily accessible on the surface of the cell; and (iv) its ABR is not significant. However, research on GT is hindered by its membrane-bound nature, which increases the difficulty to obtain crystallographic structures. Moreover, the activity assay of GT is also limited by the extremely low yield in the production of its substrate, lipid II. These factors all limited the development of GT inhibitors. With the aid of computational virtual screening on a library of 3,000,000 compounds, our research group previously discovered a potential isatin-based GT inhibitor, 2-(3-(2-Carbamimidoylhydrazone)-2-oxoindolin-1-yl)-N-(3-nitrophenyl) acetamide (10b-27), which has moderate antibacterial activity. Competitive saturation-transfer difference (STD)-NMR suggested that it binds to GT and shares the same active-site pocket with the known inhibitor moenomycin A.
In this thesis, the structure-activity relationship (SAR) of the isatin-based inhibitors was studied by further modifying the structure of 10b-27 with reference to the binding pose revealed by the GT crystal structure (PDB ID 2OLV). To achieve this goal, 20 new isatin derivatives with the aminoguanidinyl group conserved were designed and synthesized. The antibacterial activity (in terms of S. aureus MIC) showed a 4-fold enhancement when the nitrophenyl substituent was replaced by a m,p-naphthyl group. The best derivative (10-32), with the methanediylamidyl linkage removed and the substituent replaced by butyl, showed an overall 8-fold enhancement compared to 10b-27. The interaction between 10-32 and GT was confirmed by competitive saturation-transfer difference (STD)-NMR experiments. STD-NMR is one of the excellent alternatives to activity assay since it detects small molecules binding to macromolecules and does not consume the lipid II substrate. Upon addition of 10-32 into GT (100:1 ratio), strong STD-NMR signals of 10-32 were detected, suggesting that 10-32 and GT were in close contact (≤ 5 M). Further addition of moenomycin A displaced the STD signal intensities, suggested that 10-32 shares the same active-site binding pocket of GT as moenomycin A. Surprisingly, the clinically significant MRSA (ATCC® BAA-41TM) did not show any detectable resistance to 10-32, revealing its potential to be a promising antibiotic candidate. Taking into account that there are currently no GT inhibitors being used clinically, the studies of 10-32 opened up a new direction on novel antibiotic drug development.
Subjects: Hong Kong Polytechnic University -- Dissertations
Bacterial cell walls -- Synthesis -- Inhibitors
Pages: xiii, 167 pages : color illustrations
Appears in Collections:Thesis

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