Old Weapons Re-discovered
(October 31st, 2014) Antimicrobial peptides, AMPs, are ancient weapons activated by multicellular organisms against their single-celled bacterial enemies. Are they our glimmer of hope against the looming fears of antibiotic resistance?
Have you ever suffered from a bacterial tooth infection? If you’d lived 200 years ago, the pain would have put you in a ‘don’t touch me, my whole body hurts’ mood! Luckily, our generation has antibiotics, which quickly kill the pain-inducing bacteria. But for how long will they work? Antimicrobial peptides, AMP, produced by, for instance, insects and amphibians might be an alternative. In a recent paper, Alexandro Rodriguez-Rojas, Olga Makarova, and Jens Rolff from the Free University in Berlin, Germany, propose a hypothesis to explain why multicellular organisms use antimicrobial peptides at all. And how they differ from antibiotics.
AMPs are sequences of 12 to 50 amino acids. They are mostly made of hydrophobic amino acids and a couple of cationic amino acids that provide AMPs with unique bactericidal properties. In contrast to most plant and mammal outer cell membranes, which are neutrally charged, bacterial cell walls have a negative charge. Thus, cationic AMPs specifically target these negatively charged cell walls to kill the bacterium.
The authors selected Cecropin A, Melittin, magainin II, Pexiganan, LL-37 and a human lysozyme, as cationic AMPs for their study. Antibiotics Kanamycin, Ampicillin and Ciprofloxacin served as controls. One of the study’s main and most striking finding is that AMPs act so quickly that bacterial stress pathways like SOS (DNA repair with an error-prone alternative polymerase) and the similarly “mutagenic” rpoS pathway are not activated. These mechanisms are, however, primarily active under the antibiotic action and are suspected of causing antibiotic resistance. Hence, the authors suggest that it is virtually impossible for bacteria to develop AMP resistance. As a confirmation, Rolff et al. observed that AMPs have a three to four-fold lower rate of causing bacterial DNA mutation compared to antibiotics.
The present studies were performed in vitro. It’s important to note that in vitro bacterial mutation rates are considerably lower than in vivo. However, the ability of bacteria to transfer horizontally antibiotic resistance genes further supports the findings. They can also be extrapolated to other bacterial species because most bacteria share similar mutagenesis mechanisms. Another of the paper’s conclusions is that higher organisms, in symbiosis with some bacteria, use AMPs to enhance their interaction. Thus, higher organisms alter the bacterial genome in order to suit their needs. The latter idea provides new tools for evolutionary biologists’ research, even though more studies are required to confirm it.
“Employing AMPs seems advantageous for multicellular organisms, as it does not fuel the adaptation of bacteria to their immune defenses. This has important consequences for our understanding of host-microbe interactions, the evolution of innate immune defenses, and also sheds new light on antimicrobial resistance evolution and the use of AMPs as drugs,” the authors conclude. So, do you think that after the antibiotics era, a new AMP era is coming up on the horizon?