Journal
JOURNAL OF NATURAL PRODUCTS
Volume 82, Issue 9, Pages 2537-2543Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.9b00359
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Funding
- NSF MRI [CHE-1726291]
- NIH [1R01GM125814-01, T32 GM008570]
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The emergence of rapidly evolving multidrugresistant pathogens and a deficit of new compounds entering the clinical pipeline necessitate the exploration of alternative sources of antimicrobial therapeutics. Cyclotides revealed in Viola spp. are a class of highly stable, cyclic, and disulfide-bound peptides with diverse intrinsic bioactivities. Herein we have identified a novel complement of 42 putative cyclotide masses in the plant species Viola inconspicua. Cyclotide-containing fractions of a V. inconspicua peptide library revealed potent bioactivities against the Gramnegative bacteria Escherichia coli ATCC 25922 and the highly virulent and multidrug-resistant Klebsiella pneumoniae VK148. As such, six previously uncharacterized cyclotides, cycloviolacins I1-6 (cyI1-cyI6), were prioritized for molecular characterization. Cyclotides cyI3-cyI6 contain a novel TLNGNPGA motif in the highly variable loop six region, expanding the already substantial sequence diversity of this peptide class. Library fractions comprised of cyclotides cyI3-cyI6 exhibited MIC values of 18 and 35 mu M against E. coli and K. pneumoniae, respectively, whereas isolated cyI3 killed similar to 50% of E. coli at 60 mu M and isolated cyI4 demonstrated no killing at concentrations >60 mu M against both pathogens. This work expands the repertoire of bioactive cyclotides found in Viola spp. and highlights the potential of these antibacterial cyclic peptides.
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