Biomedical Engineering Reference
In-Depth Information
The work toward the production of novel balhimycin analogues has focused on
the synthesis and incorporation of analogues of several of the nonproteogenic amino
acids involved in the construction of the initial linear heptapeptide. The first
successful application of this strategy involved the creation of a mutant strain
incapable of producing
b
-hydroxytyrosine and thus unable to produce the two
diastereomeric 3-chloro-
b
-hydroxytyrosines required for balhimycin biosynthesis.
This mutant was then supplemented with several
b
-hydroxytyrosine analogues.
Through this study, the authors learned that the
p
-hydroxy group was necessary for
incorporation of these compounds, but that, as long as this functional group was in
place, the ring can be mono- (
) at various positions
(Scheme 14.5). Not only will the unnatural amino acid be incorporated, but the
resultant products also retain antibiotic activity against representative Gram-positive
bacteria [28].
A similar study was performed in which a mutant was blocked in the production
of 3,5-dihydroxyphenylglycine. Absent from any feeding, these mutants were
incapable of producing balhimycin. The ability of this mutant to accept differentially
substituted amino acids was examined by feeding 3-hydroxy-, 3-methoxy-, 3-
hydroxy-5-methoxy-, and 3,5-dimethoxyphenylglycine as well as others. This work
identified the necessity of an oxygen atom as a hydroxy or a methoxy group at the C3
position for successful incorporation. Incorporation of all these precursors led to the
successful production of bioactive tricyclic balhimycin analogues [29]. Together,
these results illustrate the potential of precursor-directed biosynthesis for the facile
production of novel compounds that are able to bypass observed resistance mechan-
isms in MRSA bacteria [30].
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,
22
) or difluorinated (
21
14.4.2.2. Erythromycin There are few compounds on which investigations into
the potential for derivatization by precursor-directed approaches have been so
numerous as they have been for erythromycin
. The first of the macrolide
antibiotics to become commercially available, erythromycin, has been used for
more than half a century in the treatment of infection. The toxicity profile and the
spectrum of this compound are so favorable that it has spawned several subsequent
generations of semisynthetic antibiotics with improved pharmacokinetics, spectrum,
and activity. The newest of these compounds, telithromycin, was approved for sale by
the FDA in 2004 [31].
The native host from which erythromycin was isolated is yet another actino-
mycete
Saccharopolyspora erythraea
. Synthesis of the aglycone core is catalyzed by
the 6-deoxyerythronolide B synthase (DEBS), arguably the best characterized PKS
(Scheme 14.6). This enzymatic assembly line is primed with propionyl-CoA and
undergoes six rounds of elongation with methylmalonyl-CoA extender units. The
complete linear polyketide is then cyclized by a terminal thioesterase, yielding 6-
deoxyerythronolide B (6-dEB). This aglycone is further processed by stereoselective
hydroxylation of the C6 position, conjugation to mycarose and desosamine at the C3
and C5 positions, respectively, hydroxylation at the C12 position, and methylation of
mycarose to yield the final antibiotic erythromycin A.
As with most of the examples discussed thus far, the initial efforts in the
precursor-directed biosynthesis of erythromycin were undertaken in the native host.
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