Trojan‑Horse Siderophore–Teixobactin Conjugates to Defeat Gram‑Negative Superbugs

Antimicrobial resistance (AMR) could cause 10 million deaths annually by 2050, with multidrug-resistant Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa listed by WHO as critical priorities. Current antibiotics fail against these species because their outer membrane blocks entry. Teixobactin, discovered in 2015, kills Gram-positive bacteria without resistance by binding the highly conserved lipid II motif, but it cannot reach this target in Gram-negatives.SYNTH-HORSE introduces a first-in-class strategy: siderophore–teixobactin conjugates (STCs). By hijacking bacterial iron-uptake pathways—the clinically validated “Trojan Horse” mechanism—STCs deliver resistance-avoidant teixobactins into Gram-negative cells. The project will: (i) synthesise ~60 STCs across diverse teixobactin analogues, siderophores (catecholate, MECAM, DOTAM) and linkers; (ii) test antibacterial potency, bactericidal activity and resistance frequency; and (iii) validate uptake and lipid II engagement. By month 24, ≥10 optimised STCs will be delivered to tackle MDR Gram negative bacteria.The fellowship combines cutting-edge chemistry, microbiology, and industrial translation. Hosted at the University of Liverpool (leaders in synthetic teixobactins), with a 5-month secondment at HZI Germany (antibiotic uptake biology) and training at Bachem UK (green peptide synthesis, scale-up), the Fellow will gain unique interdisciplinary, intersectoral, and international (3i) expertise. Outcomes include IP-ready leads, FAIR/Green Charter-aligned workflows, high-impact publications, and wide dissemination from science to policy.Impact: SYNTH-HORSE delivers a breakthrough Gram-negative antibiotic platform, transforms the researcher into a future AMR leader, and contributes to EU missions on health, innovation, and sustainability.