ABSTRACT
IMPORTANCE OF THE FIELD: New antibiotics are needed to overcome microbial resistance and to improve on the therapeutic index and clinical effectiveness of existing agents. AREA COVERED IN THIS REVIEW: This review covers the journal and patent literature published from about the mid-2000s to 2010 to provide an overview of the large diversity of new chemical entities in the macrolide, lincosaminide and streptogramin B (MLS(B)) class. WHAT THE READER WILL GAIN: The review identifies areas of the greatest effort and recent results in pursuing structure-activity relationships among MLS(B) antibiotics and highlights preclinical and clinical candidates that have arisen from these diverse discovery programs. TAKE HOME MESSAGE: Research on the MLS(B) class appears promising for the eventual registration and commercialization of several new antibiotics that improve the clinical effectiveness of existing agents and combat antibiotic-resistant pathogens.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Lincosamides/therapeutic use , Macrolides/therapeutic use , Streptogramin B/analogs & derivatives , Streptogramin B/therapeutic use , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/microbiology , Drug Discovery , Drug Resistance, Microbial/drug effects , Humans , Lincosamides/pharmacology , Macrolides/pharmacology , Streptogramin B/pharmacologyABSTRACT
We describe the first solid-phase synthesis of dihydrovirginiamycin S(1), a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.
