Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever‐increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide‐based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram‐positive pathogens and Mycobacterium tuberculosis , including drug‐resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l ‐ allo ‐End, natural teixobactin, representative teixobactin analogs, as well as the structure–activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.