December 1st, 2011 Meeting
Nihal Altan-Bonnet, Rutgers
University
Viral interior design: Rewiring the
host to generate organelle platforms for replication.
Many RNA viruses upon infecting the host, generate
membrane-bound replication organelles derived from the host's intracellular
membranes. The membrane surface of these organelles are then used as a platform
on which viral replication machinery is assembled and viral RNA is synthesized.
We have been investigating the lipid microenvironment of these replication
platforms to identify panviral features that facilitate viral RNA synthesis. We
have recently discovered that diverse set of RNA viruses all rely on host
phosphatidylinositol 4- kinases for replication. Specific viral proteins selectively
hijack these host enzymes, recruiting them to the replication membranes, in
order to generate a PI4P lipid enriched microenvironment. We will discuss the
role of PI4P lipids in viral replication, designing antiviral therapeutics
targeting the production of PI4P lipids and how studying viral biology can
provide insight into cellular biology.
Prakash Masurekar, Rutgers University
Thiazolyl Peptide Antibiotics:
Discovery of New Members and their Biological Characterization
In 1940-1950 era there was a major effort to find
antibiotics active against penicillin resistant pathogens, which have been then
recently discovered. During this
campaign, thiazolyl peptide antibiotics were discovered. Micrococcin was found in 1948 and the best
known member of this group, Thiostrepton in 1955. These are produced by Actinomycetes,
especially by the members of the genus Streptomyces.
By 2005 over 76 members of this class of antibiotics have been found. They are
very potent inhibitors of protein synthesis in Gram positive bacteria, with
in vitro Minimum Inhibitory
Concentration (MIC) below µg/ml. However
they could not be developed as clinical agents due to poor physicochemical
properties, especially the lack of water solubility. In 2003 the scientists from Bristol Meyer
Squibb Company reported discovery of a new member of this group, which they
named Nocathiacin. The structure of this compound suggested a possibility of
converting it into a water soluble derivative.
They also indicated that there may be more related compounds present in
the fermentation broth. With the
possibility in mind that one of them may be better suited for the development
of a clinical candidate we examined this culture further and found a new
antibiotic which had an amino sugar moiety.
This compound was isolated and chemically and biologically
characterized. We noted that the in
vitro MIC values were in nanogram/ml range, even against methicillin resistant
Staphylococcus aureus (MRSA). The
compound was also effective against pathogens resistant to antibiotics which
were protein synthesis inhibitors. The
compound had in vivo activity against
S. aureus
infection in mice. We confirmed that it inhibits protein synthesis and
identified the putative binding site in 23S rRNA. We isolated mutants of
S. aureus resistant to thiazomycin and used one of them to develop
a screen to find new antibiotics with the same target. We found a new antibiotic with this
screen. Unfortunately, thiazomycin could
not be developed further.
Princeton
University
Mechanisms of Hg(II) uptake and
methylation in anaerobic bacteria
Methylmercury is a potent neurotoxin which is biomagnified in aquatic biota posing health risks to humans and predatory animals. While methylmercury is typically only a small fraction of the total mercury in the environment, its production by anaerobic bacteria is a key link between mercury contamination and its health and environmental impacts. The exact mechanism responsible for Hg(II) uptake and methylation in these bacteria have remained elusive; however, some recent studies with iron and sulfate-reducing bacteria have begun to question the passive diffusion model for Hg(II) uptake previously proposed. Instead, active Hg(II) transport appears to be an important route for internalization of Hg, with differences in specificity observed across various anaerobic bacteria. These data provide further insight into the important factors controlling methylmercury accumulation in the environment.