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Microbial Membrane-Permeating Peptides and Their Applications 389
resistance and resistance to antimicrobial peptides does not appear to arise rapidly.
57,58 This is probably because the antimicrobial peptide-killing mechanisms are
largely distinct from those of small molecule antibiotics and antimicrobial peptides
are typically cidal rather than static above their threshold concentration for activity.
Another advantage with antimicrobial peptides is that their cell-permeating activities
can potentiate conventional antibiotics when used in combination. 57
As with all new drug ideas, several levels of difficulty exist with antimicrobial
peptide development and the problems apply to most potential applications of cellpermeating
peptides. Natural antimicrobial peptides are produced at site or delivered
to the place of infection by white blood cells that produce the peptides, whereas
peptides used as drugs must find their own way. Cell-permeating peptides are larger
than most drugs and typically show poor stability and distribution properties in the
body. Other problems are the uncertain design and development rules for antimicrobial
peptides, in vitro studies provide only poor indications of in vivo efficacy, and
peptides can be expensive to produce and purify. Because of these problems, screening
efforts that show initial success can prove ultimately disappointing.
Given the uncertain mixture of positive and negative properties of antimicrobial
peptides, the area is still regarded as rather risky and large pharmaceutical companies
have shown relatively little interest (Table 18.2). Nevertheless, evidence from animal
studies and clinical trials shows that antimicrobial peptides can provide effective
antimicrobials. 59-63 Also, many problems that limit efficacy in vivo and efficient large
scale production have been solved. 1 Finally, it has been very difficult to develop
effective new small molecular weight antimicrobials that do not succumb to resistance.
64,65 Therefore, whereas the unconventional nature of antimicrobial peptides
creates difficulties for clinical development, it is important to recognize that the
unique properties of these peptides also provide very valuable alternative strategies.
For the future, it seems likely that we will soon see drug approval for antimicrobial
peptides for topical or oral therapy.
18.5.2 MICROBIAL CELL-PERMEATING PEPTIDES AS CARRIERS
FOR FOREIGN SUBSTANCE DELIVERY
Microbial cells are typically very resistant to foreign substance uptake. As discussed
above, this resistance is provided by the outer cell wall, which acts as a sieve blocking
entry of many harmful compounds found in microbial environments. 12,66 Only small
molecular weight substances are able to efficiently enter microorganisms by diffusion
alone. Unfortunately, these barriers also limit the cell uptake of antimicrobial agents
that otherwise would be useful in medicine. Most antibiotics and antimicrobials used
in the clinic are small molecular weight substances, less than 500 g per mol. The
observation that antimicrobial peptides can permeate cell barriers is surprising and
opens possibilities to use these peptides to expand the range of substances that could
be used as drugs against microorganisms.
The idea of using peptides to deliver foreign substances into microorganisms
was introduced almost 30 years ago. The initial idea was to use two or three residue
peptides that are substrates for oligopeptide permeases and link impermeant toxic
compounds to the peptides for delivery (Figure 18.5). Impressive results were