Abstract
Frequent occurrences of multi-drug resistance of pathogenic Gram-negative bacteria threaten human beings. The CMP-2-keto-3-deoxy-d-manno-octulosonic acid biosynthesis pathway is one of the new targets for antibiotic design. 2-Keto-3-deoxy-d-manno-octulosonate cytidylyltransferase (KdsB) is the key enzyme in this pathway. KdsB proteins from Burkholderia pseudomallei (Bp), B. thailandensis (Bt), Pseudomonas aeruginosa (Pa), and Chlamydia psittaci (Cp) have been assayed to find inhibitors. Interestingly, Rose Bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) was turned out to be an inhibitor of three KdsBs (BpKdsB, BtKdsB, and PaKdsB) with promising IC50 values and increased thermostability. The inhibitory enzyme kinetics of Rose Bengal revealed that it is competitive with 2-keto-3-deoxy-manno-octulosonic acid (KDO) but non-competitive against cytidine 5′-triphosphate (CTP). Induced-fit docking analysis of PaKdsB revealed that Arg160 and Arg185 together with other interactions in the substrate binding site seemed to play an important role in binding with Rose Bengal. We suggest that Rose Bengal can be used as the scaffold to develop potential antibiotics.
| Original language | English |
|---|---|
| Pages (from-to) | 1414-1421 |
| Number of pages | 8 |
| Journal | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Volume | 35 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Jan 2020 |
Bibliographical note
Publisher Copyright:© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Keywords
- 2-keto-3-deoxy-d-manno-octulosonate cytidylyltransferase (KdsB)
- CMP-2-keto-3-deoxy-d-manno-octulosonic acid biosynthesis pathway
- Rose Bengal
- melioidosis
- multi-drug resistance