Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics.

摘要: ConspectusContinued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive comprehensive action is required to slow down spread antibiotic resistance, including increased investment in discovery, sustainable policies that provide returns for newly launched antibiotics, public education reduce overusage especially livestock agriculture. Without significant changes current pipeline, we are danger entering post-antibiotic era.In this Account, summarize our recent efforts develop next-generation streptogramin lankacidin antibiotics overcome bacterial by means modular chemical synthesis. First, describe highly modular, scalable route four natural group A streptogramins 6-8 steps from seven simple building blocks. We next application synthesis novel library informed vitro vivo biological evaluation high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity against longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate combination rational design can revitalize classes limited naturally arising mechanisms.Second, recount approaches toward antibiotics. Lankacidins polyketide products with several strains Gram-positive bacteria but have not been deployed as therapeutics due their instability. diastereomers 2,18-seco-lankacidinol B linear sequence ≤8 blocks, resulting revision C4 stereochemistry. detail diastereoisomers iso-lankacidinol resulted structural reassignment product. These revisions raise interesting questions about biosynthetic origin lankacidins, all which possessed uniform stereochemistry prior these findings. Finally, ability iso- seco-lankacidins inhibit growth translation vitro, providing important insights into structure-function relationships class.