Molecular mechanism of action of small molecule SMT-738 on bacterial lipoprotein transporter LolCDE

Haotian Li, Xiaojing Zhu, Dongdong Zhang, Xiaofeng Duan, Jiahui Li, Yao Qu, Danyang Li, Zhengyu Zhang, Haohao Dong, Feng-Biao Guo & Changjiang Dong  

NatureCommunications 2026

https://www.nature.com/articles/s41467-026-69411-2

Abstract

SMT-738 is a small molecule with promising antibacterial activity against Enterobacteriaceae, including multi-drug-resistant Escherichia coli. Mutations in genes encoding the lipoprotein transport complex (LolCDE) confer resistance to SMT-738. Here, we report the cryogenic electron microscopy structure of the LolCDE-SMT-738 complex at a high resolution. We use mutagenesis, drug resistance assays, biochemical assays, and molecular dynamics simulations to show that SMT-738 binds to the periplasmic end of the LolCE transmembrane domains. This binding induces an allosteric conformational change in the cytoplasmic end of the LolCE transmembrane domains and the coupling helices, leading to dissociation of one LolD subunit from the LolCDE complex. This structural disruption results in a “deadlock” of the LolCDE complex, rendering a transport-incompetent state. Our findings also provide insights into the mechanism of SMT-738 resistance and selectivity.