Research Article

Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol

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Science  12 Jun 2020:
Vol. 368, Issue 6496, pp. 1211-1219
DOI: 10.1126/science.aba9102

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Drug inhibition of glycosyltransferases

Mycobacteria, including the species that causes tuberculosis (TB), synthesize a complex cell wall that helps to support and protect the bacterial cells. The major components of the cell wall include complex heteropolysaccharides that are synthesized in the periplasmic space. Zhang et al. determined the cryo–electron microscopy structures of two transmembrane glycosyltransferase enzyme complexes that use a lipid-anchored sugar donor to append arabinose units to the cell wall polysaccharides. They also captured the anti-TB drug ethambutol bound within these complexes and observed that it binds in a site overlapping both donor and acceptor sugars. Mapping of resistance mutants provides a structural understanding of how resistance emerges while preserving function of the enzyme and may help to guide the development of next-generation anti-TB drugs that target these enzymes.

Science, this issue p. 1211

Abstract

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo–electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.

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