Biomedical Engineering Reference
In-Depth Information
Despite the success of this approach, many systems are not particularly amenable to
such manipulation, and the introduction of more complex precursor molecules that
get processed by a smaller portion of the biosynthetic pathway has shown more
promise. This section is devoted to such examples. The precursor molecules used in
these types of systems require some synthetic effort.
14.4.2.1. Balhimycin The glycopeptide antibiotic balhimycin
is closely
related to the well-known antibacterial agent vancomycin. Glycopeptides are cur-
rently considered to be among the “antibiotics of last resort” available to modern
medicine in the fight against pathogenic Gram-positive bacterial infection. With the
discovery and proliferation of
Enterococci
and
Staphylococci
that are resistant to
glycopeptides, efforts to discover new andmore effective compounds have intensified
over the past decade. Isolated from
Amycolatopsis mediterranei
, balhimycin, like
vancomycin, exerts its antibiotic action through preventing the cross-linking reactions
necessary for the formation of peptidoglycan, an essential structural feature of the cell
walls of Gram-positive bacteria.
Balhimycin biosynthesis takes place by a mechanism common among
glycopeptides in that a linear heptapeptide is constructed by the initial NRPS. In
order of incorporation, this heptapeptide consists of
N
-methyl-(
R
)-leucine, (
R
)-3-
chloro-
b
-hydroxytyrosine, (
S
)-asparagine, two molecules of (
R
)-4-hydroxyphenyl-
glycine, (
S
)-3-chloro-
b
-hydroxytyrosine, and finally (
S
)-3,5-dihydroxyphenylgly-
cine (Scheme 14.5). After the construction of this linear heptapeptide, the molecule
undergoes three oxidative cross-linking reactions to yield the tricyclic aglycone and a
final conjugation of a disaccharide to give the final bioactive molecule [27].
19
HO
OH
OH
NH
2
HO
HO
O
O
R
2
Cl
O
H
2
N
O
O
R
3
R
3
OH
R
2
R
1
N
O
OH
R
2
R
1
O
O
R
3
N
OH
A. Balhimycine mutants
H
H
NH
N
O
O
O
H
2
N
O
HO
NH
NH
2
O
R
5
O
O
R
5
OH
OH
R
4
R
4
19
(R
1
= Cl; R
2
= H; R
3
= H; R
4
= OH; R
5
= OH)
20
(R
1
= F; R
2
= H; R
3
= H; R
4
= OH; R
5
= OH)
21
(R
1
= F; R
2
= F; R
3
= H; R
4
= OH; R
5
= OH)
22
(R
1
= H; R
2
= H; R
3
= F; R
4
= OH; R
5
= OH)
23
(R
1
= Cl; R
2
= H; R
3
= H; R
4
= H; R
5
= OH)
24
(R
1
= Cl; R
2
= H; R
3
= H; R
4
= H; R
5
= OMe)
SCHEME 14.5
Precursor-directed biosynthesis of selected balhimycin analogues.
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