Target-Based Antimicrobial Drug Discovery - Bacterial Pathogenesis: Methods and Protocols - page 257

3.2. The Cell Wall
In the dawn of antimicrobial research, the cell wall was recognized as an
ideal target for chemotherapy (13) . The cell was has two significant advantages
as a target for an antibacterial agent: its building blocks primarily consist of
components external to the cell, thus allowing easy target access, and it has
no eukaryotic counterpart, ensuring selectivity and a large therapeutic window
(14) . Among the earliest antibiotics recognized for human use was penicillin,
a member of the beta-lactam antibiotics, which targets components involved
in the final step of cell wall assembly, called for obvious reasons, penicillin-
binding proteins. These proteins have been exploited by multiple generations of
beta-lactam antibiotics, both natural and derived from target-based design, and
represent a cornerstone of antimicrobial chemotherapy. More recently, resis-
tance mechanisms involving beta-lactamases, enzymes capable of degrading
beta-lactam antibiotics, have presented a challenge for this class of agents (15) .
This has led to combination therapy in which an agent targeting a penicillin-
binding protein is combined with an agent that inhibits its corresponding beta-
lacatamase, that is, a two-target attack in tandem.
The penicillin-binding proteins are by no means the only viable targets
within the cell wall. One of the most essential antibiotics in the modern arsenal,
vancomycin, is a glycopeptide natural product that binds to the D-Ala-D-Ala
dipeptide terminus of peptidoglycan precursor lipid II (16) . Other glycopeptides
or related antibiotics currently in use or under development similarly target
the transglycosylation step that occurs external to the membrane (17) . Other
accessible targets include MurG, which is membrane associated and inhibited
by ramoplanin. Perhaps more difficult to target and thus less exploited are
enzymes involved in the earlier steps of cell wall synthesis catalyzed by MurA-
MurF. In large part, a reason these enzymes have been less exploited by “cell
wall” drug discovery efforts is that they are internally located. Nonetheless,
as described below, most commercial antimicrobials target enzymes/pathways
within the cell, suggesting that MurA-MurF are excellent targets. Indeed, an
inhibitor of this pathway, fosfomycin, has in fact been developed (18) .
3.3. Translation
The most fertile source of antibacterial targets to date is the ribosome
(14,19) . From the early aminoglycosides to linezolid, a member of one of
the newest classes of antibiotics, the bacterial protein synthetic machinery has
been widely exploited. While the level of homology between bacteria and
eukaryotic organisms is strong enough to support conserved function (20) ,
the divergence is enough to afford a tolerable window of safety and to make
the ribosome a rich source for target-driven antimicrobial drug discovery.