| Autor: |
Maxson T; †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States., Deane CD; †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.; ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States., Molloy EM; ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States., Cox CL; ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.; §Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States., Markley AL; ∥Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States., Lee SW; ⊥Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States., Mitchell DA; †Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.; ‡Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.; §Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States. |
| Abstrakt: |
Streptolysin S (SLS) is a post-translationally modified peptide cytolysin that is produced by the human pathogen Streptococcus pyogenes. SLS belongs to a large family of azole-containing natural products that are biosynthesized via an evolutionarily conserved pathway. SLS is an important virulence factor during S. pyogenes infections, but despite an extensive history of study, further investigations are needed to clarify several steps of its biosynthesis. To this end, chemical inhibitors of SLS biosynthesis would be valuable tools to interrogate the various maturation steps of both SLS and biosynthetically related natural products. Such chemical inhibitors could also potentially serve as antivirulence therapeutics, which in theory may alleviate the spread of antibiotic resistance. In this work, we demonstrate that FDA-approved HIV protease inhibitors, especially nelfinavir, block a key proteolytic processing step during SLS production. This inhibition was demonstrated in live S. pyogenes cells and through in vitro protease inhibition assays. A panel of 57 nelfinavir analogs was synthesized, leading to a series of compounds with improved anti-SLS activity while illuminating structure-activity relationships. Nelfinavir was also found to inhibit the maturation of other azole-containing natural products, namely those involved in listeriolysin S, clostridiolysin S, and plantazolicin production. The use of nelfinavir analogs as inhibitors of SLS production has allowed us to begin examining the proteolysis event in SLS maturation and will aid in further investigations of the biosynthesis of SLS and related natural products. |
