Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development

Since the start of the 21st century, antibiotic drug discovery and development from natural products has experienced a certain renaissance. Currently, basic scientific research in chemistry and biology of natural products has finally borne fruit for natural product-derived antibiotics drug discovery. A batch of new antibiotic scaffolds were approved for commercial use, including oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003), and mutilins (retapamulin, 2007). Here, we reviewed the thiazolyl peptides (thiopeptides), an ever-expanding family of antibiotics produced by Gram-positive bacteria that have attracted the interest of many research groups thanks to their novel chemical structures and outstanding biological profiles. All members of this family of natural products share their central azole substituted nitrogen-containing six-membered ring and are classified into different series. Most of the thiopeptides show nanomolar potencies for a variety of Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonia (PRSP). They also show other interesting properties such as antiplasmodial and anticancer activities. The chemistry and biology of thiopeptides has gathered the attention of many research groups, who have carried out many efforts towards the study of their structure, biological function, and biosynthetic origin. Here we reviewed a total of 119 natural thiopeptides discovered during the last 50 years. Moreover, we summarized biological profiles, mechanisms of action, and biosynthesis of these thiopeptides.