Chemical synthesis enables biochemical and antibacterial evaluation of streptolydigin antibiotics

Sergey V. Pronin, Anthony Martinez, Konstantin Kuznedelov, Konstantin Severinov, Howard A. Shuman, Sergey A. Kozmin

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Inhibition of bacterial transcription represents an effective and clinically validated anti-infective chemotherapeutic strategy. We describe the evolution of our approach to the streptolydigin class of antibiotics that target bacterial RNA polymerases (RNAPs). This effort resulted in the synthesis and biological evaluation of streptolydigin, streptolydiginone, streptolic acid, and a series of new streptolydigin-based agents. Subsequent biochemical evaluation of RNAP inhibition demonstrated that the presence of both streptolic acid and tetramic acid subunits was required for activity of this class of antibiotics. In addition, we identified 10,11-dihydrostreptolydigin as a new RNAP-targeting agent, which was assembled with high synthetic efficiency of 15 steps in the longest linear sequence. Dihydrostreptolydigin inhibited three representative bacterial RNAPs and displayed in vitro antibacterial activity against S. salivarius. The overall increase in synthetic efficiency combined with substantial antibacterial activity of this fully synthetic antibiotic demonstrates the power of organic synthesis in enabling design and comprehensive in vitro pharmacological evaluation of new chemical agents that target bacterial transcription.

Original languageEnglish
Pages (from-to)12172-12184
Number of pages13
JournalJournal of the American Chemical Society
Volume133
Issue number31
DOIs
Publication statusPublished - 10 Aug 2011
Externally publishedYes

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