Endogenous cationic antimicrobial peptides (CAMPs) are among the most ancient and efficient components of host defence. It is somewhat of an enigma that bacteria have not developed highly effective CAMP-resistance mechanisms, such as those that inhibit many therapeutic antibiotics. Here, we propose that CAMPs and CAMP-resistance mechanisms have co-evolved, leading to a transient host–pathogen balance that has shaped the existing CAMP repertoire. Elucidating the underlying principles of this process could help in the development of more sustainable antibiotics.
Host–pathogen interactions are a result of long-term co-evolution and adaptation processes. Endogenous cationic antimicrobial peptides (CAMPs) such as defensins, cathelicidins and kinocidins are produced by virtually all classes of organisms and belong to the oldest and most effective components of antimicrobial host defence. Host CAMPs and bacterial CAMP-resistance mechanisms represent an intriguing example of host–pathogen co-evolution.
CAMP genes are subject to positive selection and CAMPs belong to the most rapidly evolving group of mammalian proteins, with major differences even between primate species. Some CAMPs are conserved throughout the various mammalian lineages, whereas others seem to have appeared, disappeared or expanded by gene multiplication in a subset of mammalian families.
Several bacterial pathogens can resist certain CAMPs to some extent by, for example, proteolytic cleavage, CAMP-specific binding or extrusion mechanisms, or by modifications to the bacterial surface that reduce the affinity for CAMPs. However, it is still unclear how the emergence and adaptation of microbial CAMP-resistance mechanisms has affected the evolution of CAMPs.
It is proposed that the emergence of bacterial CAMP resistance has had a profound effect on the evolution of CAMP variants. The introduction of stabilizing disulphide bridges into CAMPs, extensive variation of peptide sequences and adaptation of the electrostatic properties of CAMPs might contribute to the ongoing development of host strategies to circumvent microbial CAMP resistance, leading to continuously effective antimicrobial peptides.
Drawing the correct conclusions from the ongoing effectiveness of CAMPs might help to avoid the rapid loss of efficacy of therapeutic antibiotics and to design new, 'smarter' antibiotics. In addition to the proposed host-adaptation strategies, conceptual differences between the mode of action of CAMPs and antibiotics might have played key roles in the extraordinary success of CAMPs during evolution.
The combination of two or more antimicrobial mechanisms in one molecule, the targeting of essential, non-protein bacterial structures such as the cytoplasmic membrane, and the availability of CAMPs in high concentrations at sites of infection, could have been major obstacles for bacteria to develop highly effective CAMP resistance. Incorporating such properties into novel therapeutic antibiotics represents a major challenge for future antimicrobial drug design.
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We would like to thank our co-workers and collaborators for help and support. Our research is supported by grants from the German Research Foundation, the European Union, the German Ministry of Education and Research, the IZKF program of the Medical Faculty, University of Tübingen, and the BONFOR program of the Medical Faculty, University of Bonn.
The authors declare no competing financial interests.
Entrez Genome Project
A linear peptide that is also known as human cationic protein 18 (hCAP18). It is the only member of the cathelicidin family of antimicrobial peptides in humans.
A linear antimicrobial peptide produced by amphibians.
A linear antimicrobial peptide produced by insects and other invertebrates.
An antimicrobial peptide of diverse origin, usually adopting a sheet structure with three intramolecular disulphide bridges.
A porcine antimicrobial peptide with a sheet structure and two intramolecular disulphide bridges.
- Cryptdin-related sequence (CRS) peptide
An antimicrobial peptide produced in the mouse intestine that forms disulphide-bridge-linked homo- or heterodimers.
An antimicrobial peptide produced by Gram-positive bacteria (bacteriocin), which contains lanthionine and/or methyllanthionine amino acids with thioether bridges.
- Hepcidin-related CAMP
A vertebrate peptide with antimicrobial and iron-metabolism-regulating hormone-like activities.
An α-defensin produced by Paneth cells in the small intestine of mice.
An antimicrobial chemokine or chemokine-derived peptide from mammalian platelets.
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