Work

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

Year: 2026

Type: article

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. SMT-738 is an antibacterial compound that targets the lipoprotein transport complex (LolCDE). Here, the authors report the cryo-EM structure of the LolCDE-SMT-738 complex and use diverse techniques to provide detailed insights on the compound’s molecular mechanism of action, resistance and selectivity.

Source: Nature Communications

DOI: 10.1038/s41467-026-69411-2