Chemistry Reference
In-Depth Information
eremomycin-derived hexapeptides with other amino acids, however, did not yield
compounds of increased antibiotic activity compared with vancomycin.
118-120
Similarly, subsequent aminoacylation studies of the Nicolaou et al. with, for
example, L-Asn, L-Phe, and L-Arg, did not result in more active vancomycin
derivatives.
108
Modification of AA2 and AA6 The naturally occurring glycopeptides mostly con-
tain b-hydroytyrosines in positions 2 and 6 of the aglycon, and a varying degree of
chlorination is observed. In some cases, such as for teicoplanin but also for vanco-
mycin derivatives, AA2 can also be a tyrosine. The replacement of the b-hydroxy
group of AA2 by hydrogen, which has been found for a vancomycin analog, leads
to a two-fold decrease in antibiotic acitivity.
121
The contribution of the chlorine
atoms to antibiotic activity has been investigated already at an early stage of gly-
copeptide research. Chlorine atoms can be removed by catalytic dehalogenation
with Pd/H
2
, but these dechloro-glycopeptides have also been found in culture fil-
trates
of
bacterial
type I
glycopeptide producers. The
example of orienticin
A(X
AA2
H; X
AA6
Cl), a vancomycin-type glycopeptide, as a reference com-
(X
AA2
X
AA6
pound
compared
with
chloroorienticin
A
Cl)
and A82846B
(X
AA2
Cl; X
AA6
H), shows a five- to ten-fold reduced antibacterial activity for
orienticin A in MIC tests.
122,123
Chloroorienticin A and A82846B have comparable
antibiotic activity, which indicates a significant role for chlorine at AA2 for antibio-
tic activity compared with the less important chlorination of AA6.
17,124
A mechan-
istic explanation suggests a role of chlorine substituents supporting dimerization
and D-Ala-D-Ala-binding.
5,28,125
In this context, a co-crystal of vancomycin and
N-Acetyl-D-Ala shows that the chlorine substituent of AA6 is directed toward
the putative pocket formed by the other glycopeptide dimerization partner, which
thus contributes to an enhanced dimerization.
17,24
This aspect of substitutions at AA2 and AA6 other than chlorine has been further
investigated by Bister et al. with the example of the vancomycin-type glycopeptide
balhimycin (Scheme 2-1). The replacement of chloride salts in the culture media of
the balhimycin producer Amycolatopsis balhimycina with bromide salts rendered
the corresponding bromobalhimycin (Scheme 2-10). The use of 1:1 molar ratios
in fermentation media rendered a statistic distribution of chlorine and bromine at
AA2 and AA6, respectively. Comparative MIC tests showed similar antibiotic
activities for the bromobalhimycines compared with balhimycin.
126
Furthermore,
it was shown that this approach could be transferred to other glycopeptide produ-
cers (types II and III) to yield the corresponding bromo-glycopeptides. Because of
the toxicity of fluorine and iodine salts to glycopeptide-producing bacterial strains,
this approach could not be tested for the generation of fluorinated or iodinated
glycopeptides.
Performing mutasynthesis with the balhimycin producer Amycolatopsis balhi-
mycina, several fluorinated glycopeptides finally could be obtained.
98
The muta-
synthesis principle was established by Rinehart et al. with the example of
neomycin.
127
The experimental approach is based on the generation of directed
or undirected mutants of a secondary metabolite-producing bacterial strain, which
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