4 research outputs found
Enantioselective Synthesis of Isotopically Labeled Homocitric Acid Lactone
A concise synthesis of homocitric acid lactone was developed to accommodate systematic placement of carbon isotopes (specifically <sup>13</sup>C) for detailed studies of this cofactor. This new route uses a chiral allylic alcohol, available in multigram quantities from enzymatic resolution, as a starting material, which transposes asymmetry through an Ireland–Claisen rearrangement
Gyramides Prevent Bacterial Growth by Inhibiting DNA Gyrase and Altering Chromosome Topology
Antibiotics targeting DNA gyrase
have been a clinical success story
for the past half-century, and the emergence of bacterial resistance
has fueled the search for new gyrase inhibitors. In this paper we
demonstrate that a new class of gyrase inhibitors, the gyramides,
are bacteriostatic agents that competitively inhibit the ATPase activity
of <i>Escherichia coli</i> gyrase and produce supercoiled
DNA in vivo. <i>E. coli</i> cells treated with gyramide
A have abnormally localized, condensed chromosomes that blocks DNA
replication and interrupts chromosome segregation. The resulting alterations
in DNA topology inhibit cell division through a mechanism that involves
the SOS pathway. Importantly, gyramide A is a specific inhibitor of
gyrase and does not inhibit the closely related <i>E. coli</i> enzyme topoisomerase IV. <i>E. coli</i> mutants with reduced
susceptibility to gyramide A do not display cross-resistance to ciprofloxacin
and novobiocin. The results demonstrate that the gyramides prevent
bacterial growth by a mechanism in which the topological state of
chromosomes is altered and halts DNA replication and segregation.
The specificity and activity of the gyramides for inhibiting gyrase
makes these compounds important chemical tools for studying the mechanism
of gyrase and the connection between DNA topology and bacterial cell
division
The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives of Totarol
The synthesis and antimicrobial activity of heterocyclic
analogues
of the diterpenoid totarol are described. An advanced synthetic intermediate
with a ketone on the A-ring is used to attach fused heterocycles,
and a carbon-to-nitrogen atom replacement is made on the B-ring by
de novo synthesis. A-ring analogues with an indole attached exhibit,
for the first time, enhanced antimicrobial activity relative to the
parent natural product. Preliminary experiments demonstrate that the
indole analogues do not target the bacterial cell division protein
FtsZ as had been hypothesized for totarol
Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor
FtsZ is a guanosine triphosphatase (GTPase) that mediates
cytokinesis
in bacteria. FtsZ is homologous in structure to eukaryotic tubulin
and polymerizes in a similar head-to-tail fashion. The study of tubulin’s
function in eukaryotic cells has benefited greatly from specific and
potent small molecule inhibitors, including colchicine and taxol.
Although many small molecule inhibitors of FtsZ have been reported,
none has emerged as a generally useful probe for modulating bacterial
cell division. With the goal of establishing a useful and reliable
small molecule inhibitor of FtsZ, a broad biochemical cross-comparison
of reported FtsZ inhibitors was undertaken. Several of these molecules,
including phenolic natural products, are unselective inhibitors that
seem to derive their activity from the formation of microscopic colloids
or aggregates. Other compounds, including the natural product viriditoxin
and the drug development candidate PC190723, exhibit no inhibition
of GTPase activity using protocols in this work or under published
conditions. Of the compounds studied, only zantrin Z3 exhibits good
levels of inhibition, maintains activity under conditions that disrupt
small molecule aggregates, and provides a platform for exploration
of structure–activity relationships (SAR). Preliminary SAR
studies have identified slight modifications to the two side chains
of this structure that modulate the inhibitory activity of zantrin
Z3. Collectively, these studies will help focus future investigations
toward the establishment of probes for FtsZ that fill the roles of
colchicine and taxol in studies of tubulin