Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics

DOI: 10.1073/pnas.2319483121

Authors: Shangwen Luo (Lanzhou University) , Xin-Rong Li (Lanzhou University) , Xiao-Tong Gong (Lanzhou University) , Alexey Kulikovsky (Institute of Gene Biology, Russian Academy of Sciences) , Feng Qu (Imperial College London; Research Complex at Harwell) , Konstantinos Beis (Imperial College London; Research Complex at Harwell) , Konstantin Severinov (Institute of Gene Biology, Russian Academy of Sciences; Rutgers University) , Svetlana Dubiley (Institute of Gene Biology, Russian Academy of Science) , Xinxin Feng (Hunan University) , Shi-Hui Dong (Lanzhou University) , Satish K. Nair (University of Illinois)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 122

State: Published (Approved)
Published: January 2025

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 Escherichia coli 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 E. coli 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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: 21-ID-F at APS

Added On: 05/01/2025 11:37

Discipline Tags:

Pathogens Antibiotic Resistance Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)