Novltex: A New Class of Antibiotics with Potent Activity against Multidrug-Resistant Bacterial Pathogens─Design, Synthesis, and Biological Evaluation
Year: 2025
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Authors: Esra Malkawi, Anish Parmar, Sanjit Das, Enas Newire, Charlotte M. Jones, Kate A. Morrison, Milandip Karak, Frédéric Blanc, Nicholas Harper, Rajamani Lakshminarayanan, Zhi Sheng Poh, Navin K. Verma, Jennifer Unsworth, Dallas E. Hughes, Losee Lucy Ling, Stephen A. Cochrane, William Hope, Ishwar Singh
Institutions: Amman Arab University, University of Liverpool, Queen's University Belfast, Leverhulme Research Centre for Functional Materials Design, National University of Singapore, Singapore Eye Research Institute, Duke-NUS Medical School, Nanyang Technological University, NovoBiotic Pharmaceuticals
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: UK Research and Innovation, National Institute for Health and Care Research, Department of Health and Social Care, Rosetrees Trust, University of Liverpool, National Research Foundation, Ministry of Health -Singapore, Ministry of Education - Singapore, Ministry of Education, India, Samsung Biomedical Research Institute, National Institutes of Health, University of California, Irvine, Medical Research Council, Engineering and Physical Sciences Research Council, National Medical Research Council, Innovate UK, National Institute of Allergy and Infectious Diseases
Awards: G1167851922, G1419493264, G1941807075, G3108275046, G3468268205, EPSRC Capital Award for Core Equipment: Transformative Upgrade of NMR Facilities, G4062054595, G4281170213, Interrogating the Nisin:lipid II Interaction: A Chemical Biology Approach, G5685073141, G7016599684, G8223628023, G996242810
OpenAlex ID: W4414224789