AMP > Discussion > Relevancy of AMPs: Is there more to come?

Although at present AMPs are believed to exerttheir primary activity on bacterial membranes, new evidence is suggesting that AMP activity might be broader, including selective inhibition of intracellular targets . It is thought that cationic peptides might induce genomic responses  in bacteria treated with AMPs, in addition to any lethal effect on the bacterial membraneThis appears to be the case, as recently demonstrated (Hong et al. 2003) .These authors have shown that the  transcription profiles  of  at least 26 Escherichia coli  genes change specifically and significantly after exposure to lethal and sub lethal concentrations of Cecropin A, an emblematic cationic peptide. Moreover, half of these transcripts corresponded to proteins of unknown function, which makes these observations quite intriguing.

Now, regarding the wide variety and diverse classes of natural peptides, we must add necessarily, the processing alternatives, which are slowly being reported that might make these molecules incommensurable, approaching the diversity of immunoglobulins. The case of lactoferricin-C, generated as a functional internal domain of caprine lactoferrin in a manner mimicking the generation of inteins (selfish DNA elements inserted in-frame and translated together with their host proteins: (http://bioinfo.weizmann.ac.il/~pietro/inteins), opens a new and broad area of research. Something similar occurs with milk-derived compounds, where it is clear that milk contains a group of proteins, which perform a protective function. These proteins harbor in their primary sequence, peptides that are inactive in the parent protein and that are released during gastrointestinal digestion or food processing (Yamauchi, 1992). In contrast, the generation of thrombocidin, arising from carboxy-terminal deletions of key neuthrophil- and connective tissue-activating peptides in humans, broadens the spectrum of alternative for processing associated with the generation of AMPs. Additionally, slight variations in the structure of preexisting peptides might broaden their potential as AMPs. A good example is that of histatin-5, a naturally occurring anti-fungal peptide in human saliva, which presents at least two variants (dhvar4 and dhvar5) displaying increased anti-microbial activity by subtle changes in their amphipathicity, a good indicator of membrane destroying  activity, which allows them to be internalised showing a more destructive effect on mitochondria than on external membranes . Therefore, it is reasonable to think that a number of existing functional proteins, unrelated to immune responses, might contain potential and fully active AMPs This is a complementary strategy to that of natural anti-microbial peptides, which by themselves might adjust to potential bacterial adaptations to counteract their pathogenicity. This is only  the tip of the iceberg in this appealing topic. The recent proposalthat antibody multi specificity can be mediated by conformational diversity of pre existing isomers to increase the effective size of the antibody repertoire is perfectly applicable to understand diversity of existing AMPs as well as the potential of those derived from multiple and heterogeneous type of precursors.Only time will verify these assumptions(James et al. 2003).


References

HONG, R.W.; SHCHEPETOV, M.; WEISER, J.N.; AXELSEN, P.H. Transcriptional profile of the Escherichia coli response to the antimicrobial insect peptide cecropin A. Antimicrobial Agents and Chemotherapy, 2003, vol. 47, no. 1, p. 1-6.

YAMAUCHI, K. Biologically functional proteins of milk and peptides derived from milk proteins. Bulletin IDF, 1992, vol. 272, no. 1, p. 51-58.

JAMES C.; ROVERSI, P. and TAWFIK, D.S. Antibody multispecificity mediated by conformational diversity. Science, 2003, vol. 299, no. 5611, p.1362-1367.
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