Download Does the glycopeptide sublancin have a novel mechanism of action

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Does the glycopeptide sublancin have a novel mechanism
of action?
Emma L Denham1, Ruben A.T. Mars1, M. Tanweer
Khan1, Jörg Stülke2, Wilfred A van der Donk3
and Jan Maarten van Dijl1
1
University Medical Center Groningen, Groningen,
Netherlands 2University of Göttingen, Göttingen, Germany
3
University of Illinois, Urbana, U.S.A.
The Gram-positive bacterium Bacillus subtilis 168 produces a
potent bacteriocin active against a number of Gram-positive
pathogens including Staphylococcus aureus. The peptide must
be correctly processed for its activity. This includes removal of
the leader peptide, formation of two disulfide bonds and glucosylation of the fifth cysteine residue. Sublancin does not target
the cell wall of its target organisms and therefore we set out to
determine the mechanism by which it does inhibit growth of other
bacteria. In previous studies, we identified the MscL channel
as a key determinant for sublancin resistance. Recently, we
have expanded our knowledge on other cellular factors affecting
sublancin sensitivity or resistance. Our studies showed that
removal of the glucose phospho-transferase-system from a B.
subtilis strain sensitive to sublancin results in high resistance.
Growth on rich or minimal media containing different carbon
sources changes the sensitivity to sublancin, providing evidence
that the target of sublancin may be carbon catabolite controlled
by CcpA. Tiling array analyses revealed increased expression
of genes involved in the Sigma-B regulon and in cysteine
metabolism. Accordingly, deletion of cysK, one of the key control
factors in cysteine metabolism, results in increased sensitivity to sublancin, suggesting the level of cysteine within the cell
is important. Ongoing studies are aimed at explaining the links
between metabolism, cysteine levels within the cell and sublancin
sensitivity. The most likely targets for sublancin will be presented.