Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase

Abstract

The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

Published in

Journal of Medicinal Chemistry
2011, volume: 54, number: 14, pages: 4964-4976
Publisher: AMER CHEMICAL SOC

SLU Authors

• Mowbray, Sherry

  • Department of Molecular Biology, Swedish University of Agricultural Sciences
    
  • Uppsala University

Associated SLU-program

AMR: Bacteria

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Medical Bioscience

Publication identifier

• DOI: https://doi.org/10.1021/jm2000085

Permanent link to this page (URI)

https://res.slu.se/id/publ/46511