thiopeptide

Thiopeptides are a family of sulfur-rich, highly modified peptide antibiotics that belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) superfamily. They are characterized by densely crosslinked macrocyclic cores containing multiple thiazole and/or oxazole rings, a central nitrogen-containing heterocycle (often a pyridine), and unusual residues such as dehydroamino acids. This combination gives the molecules a rigid, polycyclic structure with potent biological activity.

Biosynthesis of thiopeptides involves ribosomal production of a precursor peptide, followed by extensive enzymatic tailoring. Post-translational modifications include cyclodehydration to form azolines and their oxidation to azoles, dehydration to dehydroalanine residues, and complex cyclizations and crosslinks that create the characteristic macrocyclic framework. These tailoring enzymes are typically encoded within dedicated gene clusters in producer organisms, most notably actinobacteria such as Streptomyces species.

Biological activity and mechanism of action of thiopeptides are primarily antibacterial. They exhibit potent activity against many Gram-positive pathogens and act by inhibiting protein synthesis, often through interactions with the bacterial ribosome or translation factors. Some members have been reported to bind to the 50S ribosomal subunit at the GTPase center, while others influence elongation factor function, illustrating a range of ribosome-targeted mechanisms.

Notable members include thiostrepton, nosiheptide, thiocillin, micrococcin, and GE2270. Thiopeptides have been studied for their therapeutic potential, though their clinical use is limited by factors such as toxicity, spectrum of activity, and pharmacokinetic properties. They continue to be of interest as scaffolds for developing new antibiotics.