One of the greatest challenges in modern healthcare is the phenomenon of antimicrobial resistance. With the ever aggravating evolution of resistance of microbes to even the most potent antibiotics like polymyxins, time has come for an introspection - introspection of the alternative strategies to combat this rising menace.
What actually is this phenomenon of “antimicrobial resistance”? Antimicrobials are compounds which inhibit the growth and multiplication of pathogenic microorganisms. Many of them are microbicidal, which means that they are intended to kill microbes. It may be possible that a single mutation in the microbe’s genome causes a change in the receptor or enzyme attacked by the antibiotic. This mutation would then confer resistance to that particular microbe. As this affects the survivability of the microbe in stressful conditions, such a mutation would be under strong natural selection, leading to the evolution of antimicrobial resistance. More indiscriminate the use of antibiotics, more stress conditions shall the microbes be subjected to, and the greater will be the selective advantage conferred by resistance causing mutations. Darwinism in action!
Why is it such a threat? Evolution of antimicrobial resistance makes the pathogenic strains non-susceptible to available antibiotics. Moreover, in environments with a tremendously large amount of antibiotic usage like hospitals, even relatively less dangerous pathogens acquire antimicrobial resistance due to continued exposure, and hence become untreatable. These are the major nosocomial pathogens which have become a menace globally, causing a huge number of fatalities due to sepsis. These pathogens include the ESKAPE pathogens - Enterococcus faecium, Staphylococcus pneumoniae, Klebsiella pneumoniae, Acinetobacter baumannii and Enterobacter sp. These feature on the WHO’s list of Top-Priority Pathogens and are associated with most of the hospital-acquired infections.
By now, you must have understood the importance of exploring novel strategies to come up with new antimicrobials. I shall limit myself to discussing in brief one of such strategies.
Most organisms are blessed with an immune system to combat pathogens. The vertebrate immune system has two interlinked arms - innate and adaptive. Out of
these two, the innate immune system is also possessed by a host of other organisms like plants, fungi, invertebrates, etc. One of the key components of the innate immune system is the production of chemical defenses against pathogens. Lysozyme present in tears is one such very popular example.
One of the other main defensive chemicals produced by living organisms is antimicrobial peptides. These are small peptides produced by cells of the body which protect the host against a variety of pathogens. In the case of humans, examples of such peptides include defensins and cathelicidins. They’re produced by neutrophils, macrophages and some other cells of the body.
Antimicrobial peptides can be alpha helices or beta sheets. Although there has been considerable research going on about the various targets of these antimicrobial peptides, scientists have unanimously concluded that whatever might be the other targets of these AMPs, they almost certainly attack the cell membrane of the microbial cells.
How do peptides affect the membrane? AMPs are mostly amphipathic, i.e. they have both hydrophilic and hydrophobic surfaces. Bacterial and fungal cell walls carry a net negative charge. Most of these AMPs have positively charged residues which get attracted to the walls of these pathogenic cells due to electrostatic attraction. Besides these charged residues, the other hydrophobic residues interact with the phospholipids of the cell membrane. They penetrate into the membrane due to hydrophobic interactions. As more and more of such peptides permeate the membrane and self associate within the membrane, they form pores in the cell membrane of the target microbe, thereby disrupting the integrity of the membrane. Boring the enemy to death in a way!
Can microbes not evolve resistance to these peptides? Well, in terms of feasibility, it is of course ‘possible’, but the probability is very less. The evolution of resistance will occur at very slow rates because it is highly difficult to alter the membrane characteristics and most of the attempts to change the membrane characteristics or membrane composition shall lead to lethality.
If the peptides already exist, what’s there to research on it then? The challenge in the therapeutic usage of these peptides is cytotoxicity. The hydrophobic part of the protein may get inserted into the cell membrane of mammalian cells as well, showing cytotoxic effects and inhibiting normal functioning of healthy cells. Non-specificity of hydrophobic interactions is a major challenge which needs to be overcome if we intend to use peptide inhibitors of pathogenic microbes. There have been instances of antimicrobial peptides which were taken to the Phase III trials but couldn’t be commercialised due to cytotoxic effects.
Hence, the work is to take this forward from here. Peptide modulators of Protein-Protein interactions can be a very promising aspect in this regard. Peptides can be made to inhibit the normal protein-protein interactions in the normal microbial membrane. Such peptides also need to be specific to the microbial membrane. To be more precise, the peptide modulators must target protein-protein interactions which do not have any homologue in the mammalian membrane. As an example, targeting such interactions in the Outer Membrane of Gram negative pathogens can be a promising strategy, as the OM of Gram negative pathogens is quite different in architecture and composition of mammalian membranes!
Such strategies are being increasingly explored to produce novel antimicrobials. Although no remarkable progress has been made to design non-cytotoxic antimicrobial peptides, efforts are underway all over the globe. New strategies, new designs, new methods of peptide synthesis, chemical modifications are continuously being tried and explored. This may have set some of my esteemed readers into thinking how could it be that despite so many attempts, we have not yet been successful. But that’s perhaps what science is - Rigour and Steady pace (not fast pace!) being its hallmarks. We may not have yet been able to come up with such a peptide, but this doesn’t stop us from dreaming of the ‘magic bullet’!
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