Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol
Lu Zhang, Yao Zhao, Yan Gao, Lijie Wu, Ruogu Gao, Qi Zhang, Yinan Wang, Chengyao Wu, Fang-Yu Wu, Sudagar S. Gurcha, Natacha Veerapen, Sarah M. Batt, Wei Zhao, Ling Qin, Xiuna Yang, Manfu Wang, Yan Zhu, Bing Zhang, Lijun Bi, Xian‐En Zhang, Haitao Yang, Luke W. Guddat, Wenqing Xu, Quan Wang, Jun Li, Gurdyal S. Besra, Zihe Rao
Abstract
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