Identification of new ClpC1-NTD binders for Mycobacterium tuberculosis drug development
Katharina Weinhäupl, Louis Meuret, Sandy Desrat, Fanny Roussi, Nelly Morellet, Sandra Beaupierre, Catherine Guillou, Carine van Heijenoort, Olga Abián, Sonia Silva Vega, Ian D. Wolf, Tatos N. Akopian, Olga Krandor, Eric J. Rubin, Adrián Velázquez‐Campoy, Diego F. Gauto, Hugo Fraga · Scientific Reports · 2025
MtbClpC1 is a promising drug target against tuberculosis. Recent studies have shown that several natural product antibiotics targeting the unfoldase N-terminal domain can impair MtbClpC1 function resulting in cell death. While the pharmacological properties of these natural product antibiotics prevent their use in the clinic, similar molecules binding to the same binding pockets can result in new drugs against Mtb. Here we demonstrate that we successfully used in silico screening to identify new ClpC1 N-terminal domain binders with micromolar affinity from a small compound library. In addition, we experimentally demonstrate that the new compounds bind to the same pockets used by the natural product antibiotics and inhibit ClpC1 function.