Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May 19;11(29):18122-18130.
doi: 10.1039/d1ra02119b. eCollection 2021 May 13.

Rational structural modification of the isatin scaffold to develop new and potent antimicrobial agents targeting bacterial peptidoglycan glycosyltransferase

Yong Wang  1 , Zhiguang Liang  1 , Yuanyuan Zheng  1 , Alan Siu-Lun Leung  1 , Siu-Cheong Yan  1 , Pui-Kin So  1 , Yun-Chung Leung  1 , Wing-Leung Wong  1 , Kwok-Yin Wong  1
Affiliations

Rational structural modification of the isatin scaffold to develop new and potent antimicrobial agents targeting bacterial peptidoglycan glycosyltransferase

Yong Wang et al. RSC Adv. .

Abstract

A series of isatin derivatives bearing three different substituent groups at the N-1, C-3 and C-5 positions of the isatin scaffold were systematically designed and synthesized to study the structure-activity relationship of their inhibition of bacterial peptidoglycan glycosyltransferase (PGT) activity and antimicrobial susceptibility against S. aureus, E. coli and methicillin-resistant Staphylococcus aureus (MRSA (BAA41)) strains. The substituents at these sites are pointing towards three different directions from the isatin scaffold to interact with the amino acid residues in the binding pocket of PGT. Comparative studies of their structure-activity relationship allow us to gain better understanding of the direction of the substituents that contribute critical interactions leading to inhibition activity against the bacterial enzyme. Our results indicate that the modification of these sites is able to maximize the antimicrobial potency and inhibitory action against the bacterial enzyme. Two compounds show good antimicrobial potency (MIC = 3 μg mL-1 against S. aureus and MRSA; 12-24 μg mL-1 against E. coli). Results of the inhibition study against the bacterial enzyme (E. coli PBP 1b) reveal that some compounds are able to achieve excellent in vitro inhibitions of bacterial enzymatic activity (up to 100%). The best half maximal inhibitory concentration (IC50) observed among the new compounds is 8.9 μM.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Three-site modified isatin derivatives for new antimicrobial studies on bacterial peptidoglycan glycosyltransferase (PGT).
Fig. 1
Fig. 1. Half maximal inhibitory concentration of compound 2 and 9 against E. coli PBP 1b.
Fig. 2
Fig. 2. Cytotoxicity evaluation for compound 2, 9, and 12 in cell proliferation of a normal human cell line BJ (ATCC CRL-2522) in 24 h treatment. Data are presented in mean ± SD of three independence experiments, each performed in triplicate.
Fig. 3
Fig. 3. (A) Docking models between inhibitors (compound 2, 6, 9 and 12) and S. aureus monofunctional glycosyltransferase (protein ID: 3HZS): moenomycin A (red), compound 2 (blue), 6 (yellow), 9 (purple), and 12 (cyan). (B) The interactions between 9 and S. aureus monofunctional glycosyltransferase were generated from AutoDock tools.
See this image and copyright information in PMC

References

    1. Hutchings M. I. Truman A. W. Wilkinson B. Antibiotics: past, present and future. Curr. Opin. Microbiol. 2019;51:72–80. doi: 10.1016/j.mib.2019.10.008. - DOI - PubMed
    1. Cho H. Uehara T. Bernhardt T. G. Beta-Lactam Antibiotics Induce a Lethal Malfunctioning of the Bacterial Cell Wall Synthesis Machinery. Cell. 2014;159:1300–1311. doi: 10.1016/j.cell.2014.11.017. - DOI - PMC - PubMed
    1. Lazar K. Walker S. Substrate analogues to study cell-wall biosynthesis and its inhibition. Curr. Opin. Chem. Biol. 2002;6:786–793. doi: 10.1016/S1367-5931(02)00355-1. - DOI - PubMed
    1. Bush K. Bradford P. A. beta-Lactams and beta-Lactamase Inhibitors: An Overview. Cold Spring Harbor Perspect. Med. 2016;6:a025247. doi: 10.1101/cshperspect.a025247. - DOI - PMC - PubMed
    1. Roca I. Akova M. Baquero F. Carlet J. Cavaleri M. Coenen S. Cohen J. Findlay D. Gyssens I. Heuer O. E. Kahlmeter G. Kruse H. Laxminarayan R. Liebana E. Lopez-Cerero L. MacGowan A. Martins M. Rodriguez-Bano J. Rolain J. M. Segovia C. Sigauque B. Tacconelli E. Wellington E. Vila J. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015;6:22–29. doi: 10.1016/j.nmni.2015.02.007. - DOI - PMC - PubMed