Chemistry Reference
In-Depth Information
N
N
N
N
O
O
N
O
O
OH
O
H
O
HN
O
O
O
O
O
HN
H
O
N
N
O
O
HN
O
S
O
N
O
HO
N
Dalfopristin (
36
)
Quinupristin (
37
)
Antibiotics from natural sources range from compounds with small molecu-
lar size (e.g., thienamycin) to large peptides (e.g., ramoplanin). They generally
possess complex architectural scaffolds and densely deployed functional groups,
which affords the maximal number of interactions with molecular targets and
often leads to exquisite selectivity for killing pathogens versus the host. This
function is nicely illustrated by vancomycin binding to its target. Vancomycin
has five hydrogen bond contacts with the D-Ala-D-Ala terminal end of pepti-
doglycan. Resistant organisms modify the terminal D-Ala with
D
-lactate, which
leads to loss of one hydrogen bond and a 1000-fold drop in binding affinity and
loss of antibiotic activity (see Fig. 12.1) (6).
12.3 ANTIFUNGAL AGENTS
Significant similarities in the fungal and mammalian cellular processes result
in very few fungal-specific drug targets that lead to the development of only a
HO
NH
2
HO
NH
2
O
O
O
O
O
O
O
O
Cl
Cl
O
O
O
O
OH
OH
HO
HO
Cl
Cl
O
O
O
O
O
O
N
N
N
N
N
N
O
O
H
H
H
H
H
H
H
H
O
O
O
O
NH
NH
H
2
NOC
H
2
NOC
HO
2
C
HO
2
C
HO
OH
HO
OH
O
−
O
O
O
N
O
R
H
O
R
H
O
O
O
N-Acyl-D-Ala-D-Ala
N-Acyl-D-Ala-D-Lactate
Figure 12.1
Vancomycin binding to the active site D-Ala-D-Ala of peptidoglycan (left
panel) and D-Ala-D-Lactate (right panel).
