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

Abstract

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.

What is the role of microbial biotechnology and genetic engineering in medicine?

“…For example, the use of iCHIP diffusion chambers, which allow for in situ bacterial growth, has facilitated the discovery of two promising new antibiotics, lassomycin, and teixobactin. These have been shown to tackle difficult Gram‐positive bacterial infections (Qi et al, 2022 ; Zhu et al, 2019 ).…”

A Review of Antibacterial Candidates with New Modes of Action

“…Recent progress in the development of teixobactin (41) analogs was reviewed in 2022. 182,183 The LolCDE ABC transporter is the inner membrane component of the Lol system, which traffics lipoproteins from the cytoplasm to the outer membrane and is essential for bacterial viability. An AstraZeneca screening campaign uncovered pyridineimidazole and pyrazole inhibitors in 2015, 184,185 while Genentech reported a pyrrolopyrimidinedione compound, G0507 (43), in 2018.…”

“…However, the levels were 2500-fold and 8-fold less than similarly evolved resistance to rifampicin, and resistance was rapidly lost without antibiotic selection. Recent progress in the development of teixobactin ( 41 ) analogs was reviewed in 2022. , …”

New Alternatives in the Fight against Tuberculosis: Possible Targets for Resistant Mycobacteria

“…Allokutzneria albata (actinomycete) Inhibits bacterial ribosome; derived macrolide antibiotic active on MDR-TB [52] Teixobactin Cyclic depsipeptide obtained from uncultured soil bacteria Blocks cell wall biosynthesis; activity against TB, including drug-resistant strains [83] Tiacumicin B…”