THCz Small molecules with antimicrobial activity that block cell wall lipid intermediates

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 47; pp. 1 - 12
• Main Authors: Reithuber, Elisabeth, Wixe, Torbjörn, Ludwig, Kevin C., Müller, Anna, Uvell, Hanna, Grein, Fabian, Lindgren, Anders E. G., Muschiol, Sandra, Nannapaneni, Priyanka, Eriksson, Anna, Schneider, Tanja, Normark, Staffan, Henriques-Normark, Birgitta, Almqvist, Fredrik, Mellroth, Peter
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.11.2021
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antibacterial materials; Antibiotic resistance; Antibiotics; Antimicrobial activity; Antimicrobial agents; antimicrobials; Bacteria - drug effects; Bactericidal activity; Biological Sciences; Biosynthesis; Cell Wall - chemistry; Cell Wall - drug effects; cell wall biosynthesis; Cell walls; Chemical synthesis; Drug Resistance, Bacterial - drug effects; Intermediates; Lipids; Lipids - chemistry; Lysis; Medicin och hälsovetenskap; Microbial Sensitivity Tests; Mode of action; N-Acetylmuramoyl-L-alanine Amidase; Peptidoglycan - biosynthesis; Peptidoglycans; Polyisoprenyl Phosphates; Polysaccharides; Scaffolds; Streptococcus pneumoniae; Streptococcus pneumoniae - drug effects; Teichoic Acids - chemistry; tetrahydrocarbazole; Undecaprenyl pyrophosphate; Uridine Diphosphate N-Acetylmuramic Acid - analogs & derivatives; cell wall biosynthesis; tetrahydrocarbazole; antimicrobials; antibiotic resistance; Streptococcus pneumoniae
• DOI: 10.1073/pnas.2108244118
• ISSN: 0027-8424; 1091-6490

Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.