Biomedical Engineering Reference
In-Depth Information
In order to modify the alkyl substitution of the macrocycle, one would alter the specii city of the
acyltransferase moiety (AT) that is responsible for recruiting these units to join the growing chain.
As shown in Figure 6.13, by swapping the genes that encode for the propionyl group to be added in
module 4 for another AT domain that is specii c for an acetyl group, it is possible to encode for an
erythromycin analog that lacks methyl substitution at position 6. In theory, similar modii cations in
alkyl substitution and oxidation state can be engineered for the other positions on the macrocycle.
ER
ER
AT module swap
DH
KR
DH
KR
ACP
KS
AT
ACP
KS
AT
DEBS module 4
DEBS module 4
AT
Propionate-speciic
AT
Acetate-speciic
O
O
OH
OH
OH
OH
OH
OH
OH
O
OH
O
O
N(CH
3
)
2
O
O
N(CH
3
)
2
O
O
O
O
O
O
O
OCH
3
OCH
3
OH
OH
Erythromycin A
6-Desmethyl-erythromycin A
FIGURE 6.13
Substitution of an acetate-specii c AT for the propionate-specii c AT in DEBS module 4 leads
to 6-desmethyl analogs.
6.5.4 S
TRUCTURE
-A
CTIVITY
R
ELATIONSHIPS
Alterations in structure, whether done by chemical synthesis or biosynthesis, result in variations in
the biological properties of the compound in comparison with the parent. Such SAR reveal the areas
of a given structure type that are optimal for driving the potency or selectivity of the series. A very
simple example of SAR observed in naturally occurring congeners is illustrated in Figure 6.14 for
the antibiotic mannopeptimycin. The mannopeptimycins are ordinarily produced as a mixture of
components, some of which contain an isovaleryl ester group on the terminal unit of the di-mannose
side chain. The bioassay data in the table are measures of antibiotic effectiveness. Minimal inhibi-
tory concentration values (MIC) are measures of antibiotic potency in vitro that are determined
by serial dilution of a solution of antibiotic substance to the point where no inhibition of growth is
obtained. This value is reported in terms of a concentration in this case in micrograms per milliliter
of the i nal test solution. The ED
50
value refers to the potency of the compound against an infection
induced in a mouse model. The lowest concentration of the dose that was still effective in protecting
the mouse is shown. The units are in milligrams of antibiotic per kilogram weight of a mouse. What
we are able to discern from these data is that the ester function is responsible for conferring a great
deal of the potency to the compounds, as alpha is considerably less potent than any of the esterii ed
components. In addition, the position of the ester group on the terminal mannose unit also has a
