Novltex: A New Class of Antibiotics with Potent Activity against Multidrug-Resistant Bacterial Pathogens─Design,...

Increasing spread of multidrug-resistant (MDR) bacteria demands antibiotics that combine potent activity with scalable synthesis. Novo29 (clovibactin) is promising but suffers from low yield (1%), dependence on costly and noncommercial d-hydroxy-asparagine (d-Hyn₅), and lengthy syntheses. We report "Novltex", a novel class of antibiotic that fuses the Leu₁₀-teixobactin macrocycle to the Novo29 N-terminus tail, replacing d-Hyn₅ with inexpensive threonine. Our efficient synthesis delivers 30% yield with faster coupling cycles (∼10 min), enabling rapid and low-cost scale-up. A 16-member analogue library systematically probing amino-acid configuration identified analogue 4 (d-Leu₂) as the initial lead, informing the rational design of analogue 12 (d-cyclohexylalanine₂). Analogue 12 displays potent antibacterial activity (minimum inhibitory concentration (MIC) 0.12-0.5 μg/mL) against World Health Organization (WHO)-priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium, surpassing several licensed antibiotics while maintaining an excellent safety profile. Lipid II-binding assays confirm the conservation of the parent mechanism. Novltex, therefore, offers a practical, high-yielding, and cost-efficient platform for the development of next-generation antibiotics targeting MDR infections.