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Title: Hydrophobic substituents on isatin derivatives enhance their inhibition against bacterial peptidoglycan glycosyltransferase activity
Authors: Wang, Y 
Cheong, W 
Liang, Z 
So, L 
Chan, K 
So, P 
Chen, YW 
Wong, W 
Wong, K 
Issue Date: Apr-2020
Source: Bioorganic chemistry, Apr. 2020, v. 97, 103710
Abstract: Moenomycin A, the well-known natural product inhibitor of peptidoglycan glycosyltransferase (PGT), is a large amphiphilic molecule of molecular mass of 1583 g/mol and its bioavailablity as a drug is relatively poor. In searching for small-molecule ligands with high inhibition ability targeting the enzyme, we found that the addition of hydrophobic groups to an isatin-based inhibitor of bacterial PGT significantly improves its inhibition against the enzyme, as well as its antibacterial activity. The improvement in enzymatic inhibition can be attributed to a better binding of the small molecule inhibitor to the hydrophobic region of the membrane-bound bacterial cell wall synthesis enzyme and the plasma membrane. In the present study, a total of 20 new amphiphilic compounds were systematically designed and the relationship between molecular hydrophobicity and the antibacterial activity by targeting at PGT was demonstrated. The in vitro lipid II transglycosylation inhibitory effects (IC50) against E. coli PBP1b and MICs of the compounds were investigated. Optimized results including MIC values of 6 μg/mL for MSSA, MRSA, B. subtilis and 12 μg/mL for E. coli were obtained with an isatin derivative 5m which has a molecular mass of 335 g/mol.
Keywords: Peptidoglycan glycosyltransferase
Publisher: Elsevier
Journal: Bioorganic chemistry 
ISSN: 0045-2068
EISSN: 1090-2120
DOI: 10.1016/j.bioorg.2020.103710
Rights: © 2020 Elsevier Inc. All rights reserved
© 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
The following publication Wang, Y., Cheong, W.-L., Liang, Z., So, L.-Y., Chan, K.-F., So, P.-K., Chen, Y. W., Wong, W.-L., & Wong, K.-Y. (2020). Hydrophobic substituents on isatin derivatives enhance their inhibition against bacterial peptidoglycan glycosyltransferase activity. Bioorganic Chemistry, 97, 103710 is available at
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