Addicted To Resistance

A lot of public attention is given over to cancer, Syringe and tablets on the paper with graph of heart rhythm - stock photogenetic disease and lolcats, but have you ever thought of what will happen if we ever run out of antibiotics? Think about it…playing football would no longer be a fun weekend activity; it could become a battle of life and death as you grapple with that infection you got from a scraped knee, an infection that modern medicine would be helpless to cure. Bacterial antibiotic-resistance is becoming a major problem. There’s no denying it. Many bacteria have evolved enzymes or have tweaked their own biology to avoid the attentions of our most-used drugs, but it’s just recently coming to light that many bacterial species have also evolved special molecular systems called Toxin-Antitoxin Systems (TA) to combat our dwindling antimicrobial arsenal.

So What Are TA?
TA are encoded in DNA as Operons, and encode a stable toxin molecule and an unstable antitoxin to combat the effect of its cognate toxin. TA can be encoded directly into the prokaryotic genome or be plasmid-borne, and each format appears to have its own function.
Plasmid-borne TA seem to have evolved to selfishly ensure the survival of the plasmid they are on. This is achieved because when a bacterial cell divides it can sometimes fail to properly dish out its plasmids to the resulting daughter cells, and without the continued transcription of the unstable antitoxin the toxin becomes active and wreaks havoc upon the plasmid-free bacterium. The effects differ between each particular system but as an example, the cell can burst, killing the cell. This is referred to as Post-Segregational Killing as it occurs after the cell has divided and, more importantly, after the separation of its plasmid DNA has occurred, akin to an addiction with lethal withdrawal symptoms1,2. Tell your mother she should be glad you’re not hooked on this stuff.

Chromosomally-encoded TA on the other hand are almost universal in the prokaryotic world, being found in many non-pathogenic and deadly bacteria such as;

  • Mycobacterium tuberculosis, the cause of TB,
  • Salmonella enterica, a major cause of food-poisoning,
  • And Escherichia coli, which can cause a variety of diseases.1,2

The wide-spread existence of TA suggests that they may be involved in more than Post-Segregational Killing, otherwise why would they be so common in the microscopic world, let alone integrated into an organism’s very genome?
It would seem that Chromosomally-encoded TA, as well as possibly killing the cell like plasmid-borne TA if they are removed, are geared towards giving environmental stress and antibiotic-resistance to bacteria. The most studied way of doing this is putting the cells into the Persistence state- a dormant, ‘sleeping’ phase where they do not grow or replicate. This phenomenon has been known of since the 1940’s3 but the cause of it was not discovered until about 20 years ago. It is now known that TA are responsible for this, and this explains why present antibiotics which mainly target growing, active cells fail to target Persistent cells.

So How Do TA Work?
There are two classes of TA, the key class here being Class II systems. Class II systems comprise unstable protein antitoxins that bind and inactivate their toxins in complexes, a prime example being the E. coli K-12 Strain’s RelBE system.
RelE is the toxin of the system that, by an unknown mechanism, blocks universal transcription of the bacterium’s genome, dampening down the cellular metabolism to result in the Persistent state. RelB is the antitoxin protein that sequesters RelE under welcome environmental conditions4.
This particular system is activated by the alarmone ppGpp in the following way. ppGpp is produced in bacterial cells under environmental stresses such as nutrient starvation and antibiotic challenge. The increase and inbalance of ppGpp in the cell inhibits the actions of PPX, an enzyme that degrades inorganic Poly-phosphate chains, or Poly-Pi. Intracellular Poly-Pi in turn activates a protease which degrades RelB to allow activation of RelE2 so that it can suppress the bacterial genome’s transcription. This puts the bacterium into a persistent, antibiotic-resistant state until environmental conditions (such as nutrient availability or the removal of antimicrobial agents) have improved.

As research shows these TA are responsible for the Persistent state of resistant pathogens, they could be highlighted as novel targets for antibiotic attack. This would mean potential treatments for hard-to-treat or recurrent infections, lifting the weight that is crushing the medical profession. And even if not, it’s still fascinating.

Like molecular heroin, they can’t get enough.
R.

  1. Gerdes K (2000). Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress. Journal of bacteriology, 182 (3), 561-72 PMID: 10633087
  2.  Bigger J.W. (1944.) “Treatment Of Staphylococcal Infections With Penicillin By Intermittent Sterilisation.” The Lancet. 244 (6320), pg. 497-500.
  3. Pedersen K, Christensen SK, & Gerdes K (2002). Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Molecular microbiology, 45 (2), 501-10 PMID: 12123459
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