2 research outputs found
Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
Mixture based synthetic combinatorial
libraries offer a tremendous
enhancement for the rate of drug discovery, allowing the activity
of millions of compounds to be assessed through the testing of exponentially
fewer samples. In this study, we used a scaffold-ranking library to
screen 37 different libraries for antibacterial activity against the
ESKAPE pathogens. Each library contained between 10000 and 750000
structural analogues for a total of >6 million compounds. From
this,
we identified a bis-cyclic guanidine library that displayed strong
antibacterial activity. A positional scanning library for these compounds
was developed and used to identify the most effective functional groups
at each variant position. Individual compounds were synthesized that
were broadly active against all ESKAPE organisms at concentrations
<2 Ī¼M. In addition, these compounds were bactericidal, had
antibiofilm effects, showed limited potential for the development
of resistance, and displayed almost no toxicity when tested against
human lung cells and erythrocytes. Using a murine model of peritonitis,
we also demonstrate that these agents are highly efficacious in vivo
The āPepSAVI-MSā Pipeline for Natural Product Bioactive Peptide Discovery
The
recent increase in extensively drug-resistant bacterial pathogens
and the associated increase of morbidity and mortality demonstrate
the immediate need for new antibiotic backbones with novel mechanisms
of action. Here, we report the development of the PepSAVI-MS pipeline
for bioactive peptide discovery. This highly versatile platform employs
mass spectrometry and statistics to identify bioactive peptide targets
from complex biological samples. We validate the use of this platform
through the successful identification of known bioactive peptides
from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum
for V. odorata cyclotides, including
antibacterial activity of cycloviolacin O2 against A.Ā baumannii. We further demonstrate the broad
applicability of the platform through the identification of novel
anticancer activities for cycloviolacins by their cytotoxicity against
ovarian, breast, and prostate cancer cell lines