Chemistry of the American Chemical Society (which document new drugs introduced
on a yearly basis) verifies this and reveals that the majority of so-called new antibiotics
developed over the past two decades continue to be penicillin and cephalosporin deriv-
atives. These grim realities attest to the worries of microbiologists and epidemiologists
who contend that “the bugs are eventually going to get us” and “our current drugs prob-
ably won’t be up to this challenge.” Clearly, the design of drugs that target exogenous
pathogens will emerge as an important drug design field in coming years.
9.1.2 Designing Drugs for Exogenous
Pathogen-Based DiseasesDesigning drugs for exogenous pathogens has some fundamental differences from the
process of designing drugs to achieve the manipulation of endogenous processes.
Exogenous pathogens represent targets for drug design that are nonself. When a drug
binds to a receptor in the human heart, the target is self; however, when a drug binds
to bacteria within lung tissue, then the target is nonself. The toxicity that the drug can
inflict upon the surrounding tissues of the receptor microenvironment is quite different
between self and nonself. It is desirable for a drug binding to a bacterium to kill that
bacterium; it is undesirable for a drug binding to heart tissue to kill cardiac cells.
The types of intermolecular interactions exploited during drug design against nonself
exogenous targets may also be different. For example, it is acceptable for a drug to bind
to a nonself target by a covalent bond. Whereas drug–receptor interactions via covalent
bonding are typically avoided for endogenous targets for reasons related to toxicity,
covalent bonds are acceptable when targeting a nonself receptor on an exogenous
pathogen. This observation is well exemplified by the example of antibacterial agents,
such as penicillin, that covalently link to the bacterial cell wall.
In developing drugs for the treatment of diseases caused by microbes, drug design
strategies may differ widely from microbe to microbe. In terms of structural complex-
ity, microbes exist on a structural spectrum (prions, viruses, bacteria, fungi, parasites),
with prions being the least complex and parasites the most complex. Drug design for
prion and viral diseases is the most challenging, since these microbes are structurally
simple. A prion is merely a protein; viruses are composed principally of nucleic acids.
Because of the structural overlap between prion proteins and viral nucleic acids and the
corresponding macromolecules found in humans, it is difficult to design a drug specific
for the microbe. At the other end of the spectrum, parasites have a structural complex-
ity (organs, rudimentary nervous system) that begins to approach the sophistication of
human cell lines. Because of this similarity, it may be difficult to identify a target that
will enable selective killing of the parasite without causing concomitant harm to the
host organism. The structurally intermediate bacteria have sufficient complexity to
enable drug design without the complexity overlapping with that of the host biochem-
istry. Accordingly, antibacterial drug design has traditionally been more successful than
drug design targeted against the other microbes.
In designing drugs for exogenous pathogens, it is sometimes possible to minimize or
even neglect pharmacokinetic design considerations. For instance, if a drug were being
designed to treat intestinal parasites, it would be beneficial to ensure that the drug is
restricted to the gastrointestinal tract and is never absorbed. The strategic use of charged or
EXOGENOUS PATHOGENS AND TOXINS 545