3 research outputs found
Total Synthesis of Glycinocins A–C
The glycinocins are a class of calcium-dependent,
acidic cyclolipopeptide
antibiotics structurally related to the clinically approved daptomycin.
Herein, we describe a divergent total synthesis of glycinocins A–C,
which differ in the structure of a branched α,β-unsaturated
fatty acyl moiety. The three natural products exhibited calcium-dependent
antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MICs ranging
from 5.5 to 17 μM
Total Synthesis of Teixobactin
The first total synthesis of the
cyclic depsipeptide natural product
teixobactin is described. Synthesis was achieved by solid-phase peptide
synthesis, incorporating the unusual l-<i>allo</i>-enduracididine as a suitably protected synthetic cassette and employing
a key on-resin esterification and solution-phase macrolactamization.
The synthetic natural product was shown to possess potent antibacterial
activity against a range of Gram-positive pathogenic bacteria, including
a virulent strain of <i>Mycobacterium tuberculosis</i> and
methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)
Marine Mammal Microbiota Yields Novel Antibiotic with Potent Activity Against <i>Clostridium difficile</i>
The
recent explosion of research on the microbiota has highlighted the
important interplay between commensal microorganisms and the health
of their cognate hosts. Metabolites isolated from commensal bacteria
have been demonstrated to possess a range of antimicrobial activities,
and it is widely believed that some of these metabolites modulate
host behavior, affecting predisposition to disease and pathogen invasion.
Our access to the local marine mammal stranding network and previous
successes in mining the fish microbiota poised us to test the hypothesis
that the marine mammal microbiota is a novel source of commensal bacteria-produced
bioactive metabolites. Examination of intestinal contents from five
marine mammals led to the identification of a <i>Micromonospora</i> strain with potent and selective activity against a panel of Gram-positive
pathogens and no discernible human cytotoxicity. Compound isolation
afforded a new complex glycosylated polyketide, phocoenamicin, with
potent activity against the intestinal pathogen <i>Clostridium
difficile</i>, an organism challenging to treat in hospital settings.
Use of our activity-profiling platform, BioMAP, clustered this metabolite
with other known ionophore antibiotics. Fluorescence imaging and flow
cytometry confirmed that phocoenamicin is capable of shifting membrane
potential without damaging membrane integrity. Thus, exploration of
gut microbiota in hosts from diverse environments can serve as a powerful
strategy for the discovery of novel antibiotics against human pathogens