Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics

Infections caused by gram-negative pathogens continue to be a major risk to human health because of the innate antibiotic resistance endowed by their unique cell membrane architecture. Nature has developed an elegant solution to target gram-negative strains, namely by conjugating toxic antibiotic warheads to a suitable carrier to facilitate the active import of the drug to a specific target organism. Microcin C7 (McC) is a Trojan horse peptide-conjugated antibiotic that specifically targets enterobacteria by exploiting active import through oligopeptide transport systems. Here, we characterize the molecular mechanism of McC recognition by YejA, the solute binding protein of the <i>Escherichia coli</i> oligopeptide transporter. Structure-guided mutational and functional analysis elucidates the determinants of substrate recognition. We demonstrate that the peptide carrier can serve as a passport for the entry of molecules that are otherwise not taken into <i>E. coli</i> cells. We show that peptide conjugation can remodel the antibiotic spectrum of clinically relevant parent compounds. Bioinformatics analysis reveals a broad distribution of YejA-like transporters in only the Proteobacteria, underscoring the potential for the development of Trojan horse antibiotics that are actively imported into such gram-negative bacteria.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-12-31
DOI
https://doi.org/10.1073/pnas.2319483121
Citations
6
Primary Topic
Antibiotic Resistance in Bacteria
Type
article
Field-Weighted Citation Impact
1.02

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics

Shangwen Luo, Shi‐Hui Dong, Konstantinos Beis, Svetlana Dubiley et al.
6 citations
Proceedings of the National Academy of Sciences
Antibiotic Resistance in Bacteria
1.02
article

Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics

Shangwen Luo, Shi‐Hui Dong, Konstantinos Beis, Svetlana Dubiley, Xiaojian Gong, Konstantin Severinov, Xinxin Feng, Satish K. Nair, Alexey Kulikovsky, Xinrong Li, Feng Qu
article en
6 citations

Abstract

Infections caused by gram-negative pathogens continue to be a major risk to human health because of the innate antibiotic resistance endowed by their unique cell membrane architecture. Nature has developed an elegant solution to target gram-negative strains, namely by conjugating toxic antibiotic warheads to a suitable carrier to facilitate the active import of the drug to a specific target organism. Microcin C7 (McC) is a Trojan horse peptide-conjugated antibiotic that specifically targets enterobacteria by exploiting active import through oligopeptide transport systems. Here, we characterize the molecular mechanism of McC recognition by YejA, the solute binding protein of the <i>Escherichia coli</i> oligopeptide transporter. Structure-guided mutational and functional analysis elucidates the determinants of substrate recognition. We demonstrate that the peptide carrier can serve as a passport for the entry of molecules that are otherwise not taken into <i>E. coli</i> cells. We show that peptide conjugation can remodel the antibiotic spectrum of clinically relevant parent compounds. Bioinformatics analysis reveals a broad distribution of YejA-like transporters in only the Proteobacteria, underscoring the potential for the development of Trojan horse antibiotics that are actively imported into such gram-negative bacteria.

Proceedings of the National Academy of SciencesVol. 122(1)
Rutgers, The State University of New Jersey (US), Rutherford Appleton Laboratory (GB), University of Illinois Urbana-Champaign (US), Hunan University (CN), Research Complex at Harwell (GB), Rutgers Sexual and Reproductive Health and Rights (NL), Quantitative BioSciences (US), Institute of Gene Biology (RU), State Key Laboratory of Applied Organic Chemistry, Imperial College London (GB), Lanzhou University (CN)
Diamond Light Source, Lanzhou University, National Natural Science Foundation of China, Russian Science Foundation, National Institutes of Health, University of Illinois at Urbana-Champaign, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 25%
Antibiotic Resistance in Bacteria
1.02
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.