Chemistry Reference
In-Depth Information
OH
OH
OH
H
H
H
H
H
H
S
S
R
N
N
N
NH
2
O
O
O
NH
2
N
CO
2
H
Thienamycin (
15
)
CO
2
H
Imipenem (
16
)
CO
2
H
Carbapenems (
17
)
S
O
H
H
2
N
NH
2
O
H
H
N
HN
OMe
OH
O
N
HO
2
C
N
HN
O
N
O
SO
3
H
O
N
O
CO
2
H
O
SO
3
H
HO
2
C
Clavulanic acid (
18
)
sulfazecin (
19
)
Aztreonam (
20
)
that would be similar to
β
-lactam antibiotics. This focus led to the discov-
eries of clavulanic acid (
18
) and monobactam sulfazecins (
19
). Nature effec-
tively stabilized the latter monobactam structure by the addition of a
N
-sulfamic
acid. The
β
-lactamase inhibitor clavulanic acid was combined with amoxicillin,
which led to the development of a potent and successful antibacterial agent,
Augmentin
®
(GSK, Surrey, UK) (10). Chemical modifications of the monobac-
tam produced aztreonam (
20
), a clinical agent with a narrow spectrum but
significantly improved activity against Gram-negative pathogens, particularly
Pseudomonas aeriginosa
(11).
Immediately after the discovery of penicillin, Waksman started efforts on
soil-dwelling bacteria and discovered the first of the aminoglycosides, strep-
tomycin (
21
) from
Streptomyces griseus
, in 1943 (6). Subsequently, a series of
aminoglycosides was isolated. These aminoglycosides are potent broad-spectrum
antibiotics and are potent inhibitors of protein synthesis. Unfortunately, nephro-
toxicity limited their wider use, and they are used mainly for treatment of
infections caused by Gram-negative bacteria. Continued efforts to screen prokary-
otic organisms led to the discovery of the phenyl propanoids (chloroamphenicol,
22
) and tetracyclines. The latter is a major class of tetracyclic polyketides that
were discovered from various species of
Streptomyces
spp. Although the parent
tetracycline (
23
) was not used as an antibiotic to a great extent, the chloro deriva-
tive (Clortetracycline
24
), oxytetracycline (
25
), and minocycline (
26
) are clinical
agents. This class of compound suffered from the selection for rapid resistance
via efflux mechanism that limited their use (6). Recently, however, chemical
modifications of the A-ring yielded compounds that overcame the efflux pump
and lead to the development of tigecycline (
27
) as an effective broad spectrum
antibiotic (12).
Another large class of orally active protein syntheis inhibitor antibiotics that
were produced by
Streptomyces
spp. is represented by 14-membered lactones
generically callsed macrolides, exemplified by the first member, erythromycin
(
28
) (6). Chemical modifications of this class of compounds led to many clinical
