Antimicrobial peptides: the naturally found sentinels against microbes


The discovery of penicillin in 1928, had transformed the face of therapeutic intervention. Innumerable lives are saved by this genre of molecular remedy, but over the past years, overuse of antibiotics has led to a mammoth problem – antibiotic resistance.  


Bacteria are becoming resistant to several potent antibiotics, raising serious concern in the healthcare system.


WHO deems (1), with no sturdy steps to curb this malice, the world could see 10 million annual deaths by 2050.



Do antibiotics have any substitutes?


When there is a will, there's a way; and nature always finds its way.


Sitting deep in our body - short (12-50 amino acids long) proteins - the antimicrobial peptides (AMPs) provide a natural shield. AMPs are present throughout nature and are associated with the innate immune response in all organisms as defence from infecting pathogens.


AMPs provide the defence mechanism in several ways. They could disrupt microbial cell walls, or rupture them by punching holes. The AMPs can also boost our immune system by adapting it to fight the invading microorganisms more efficiently.




Functions of AMPs [Source: L.J. Zhang, R.L. Gallo, Antimicrobial peptides, Curr. Biol. 26(1) .2016. R14-9.]



AMPs are ubiquitously present in many types of animals and cells, spanning from insects, to frogs, to humans.


This brings me to the exciting research from the lab of Robert Vacha of CEITEC-MU. The Vacha group studies membrane and proteins, and most importantly, the interaction between these two biological entities.


Hence, the AMPs constitutes one of their favourite research avenues, where the chances to investigate the interplay between membranes and these tiny peptides are plentiful. 



Robert Vacha



Unique AMPs from the African Clawed frog


Magainin, a class of AMPs, isolated from the skin of African clawed frog Xenopus laevis, is one of the extensively studied AMP classes. The AMPs named Magainin 2 (MG2A) and PGLa belong to this particular class.


Several AMPs act better when they work together (synergistic response) with another AMP. A perfect case of antimicrobial synergy is seen between MG2A and PGLa.


A couple of years back, the Vacha group put forward the biophysical mechanism (2) of this synergistic duo against a gram-negative bacterial membrane.


Backed by experimental and computational analysis, the research showed that PGLa acts as a ‘helper molecule’, which clears the path for MG2A by preconditioning the membrane for a useful perturbation.



The follow-up studies


Recently, two back-to-back research publications (3,4) from the Vacha lab had strengthened our knowledge of the biophysical framework of this synergism.


In the first paper (3), Pachler and colleagues showed that even with low concentrations, the peptide-couple could considerably perturb membrane integrity. Moreover, the formation of an MG2A-PGLa homodimer makes it easier for the peptides to result in higher membrane distress.


The subsequent study (Kabelka et al., 4) examines the structural changes the membrane features upon its interaction with the AMPs. The peptide dimers first cause synergistic membrane adhesion followed by fusion of membranes and eventually ending in a sponge phase (a disordered membrane form) which becomes easily leaky.



Where can we employ the acquired knowledge?


Antimicrobial peptides have great potential to be applied to strategize new antimicrobial and anti-infection treatments and therapies.


The beauty of creating a peptide-based therapy is that they are naturally available.


90% of AMPs could be toxic. However, thanks to nature, as peptides, they are naturally degradable, and our body can digest them. Unfortunately, this also decreases their efficacy.

To solve this issue, peptide-based molecules, which are qualified as drugs, are cyclic peptide or peptides with other modifications, making them difficult to digest.


On that note, implementing the gathered information about the combined efficacy of the MG2A-PGLa pair, Dr Vacha and researchers are seeking to develop more potent novel AMPs


Which is a steady stride against Antibiotic resistance!



References

  1. https://www.who.int/news-room/detail/29-04-2019-new-report-calls-for-urgent-action-to-avert-antimicrobial-resistance-crisis
  2. Leber, R., M. Pachler, et al. 2018. Synergism of antimicrobial frog peptides couples to membrane intrinsic curvature strain. Biophys. J. 114:1945–1954.
  3. Pachler, M.; Kabelka, I, et al. 2019. Magainin 2 and PGLa in Bacterial Membrane Mimics I: Peptide-Peptide and Lipid-Peptide Interactions. Biophysical Journal. 117, 1858–1869.
  4. Kabelka, I.; Pachler, M.; Prévost, S. et al. 2020. Magainin 2 and PGLa in Bacterial Membrane Mimics II: Membrane Fusion and Sponge Phase Formation. Biophysical Journal. 118, 3, 612-623



Written by Somsuvro Basu


Publication date: 30.04.2020