Oct 17 2013

PPMOs – The New Antibiotic?

People generally worry too much and about the wrong things. The media exploits dramatic risks for sensational headlines and exciting narratives, but rarely put risks into a useful context.

Meanwhile, there are some real things to be worried about out there. One thing that has long been on my short list is the coming post-antibiotic era.

Antibiotics have dramatically improved human life and life-expectancy. I know many people who would likely be dead without them. The are one of modern medicines greatest success stories. But they have a critical weakness – evolution.

The antibiotic era started an evolutionary arms race with the pathogenic bacteria they kill or inhibit – and the bacteria are winning. Antibiotics work through a number of mechanisms that interfere with the cellular function of prokaryotes, but not eukaryotes, so bacteria are affected while host cells are unharmed.

These antibiotics create selective pressure, however, and because bacteria reproduce so quickly, there are lots of opportunities for beneficial mutations to arise. In addition bacteria often have part of the genetic code in the form of plasmids – self-contained DNA strands that can be shared between different species of bacteria.

This means that if one strain of bacteria evolves resistance to a specific antibiotic, it can share that resistance to other strains and even other species through plasmids. Resistance can therefore spread, and does not have to re-evolve in each strain.

Plasmids can even contain mutations for resistance to multiple different antibiotics, the use of any one of which can result in the spread of multi-drug resistance.

We already are dealing with highly resistant strains of bacteria, which is an increasingly difficult problem. There are several partial solutions to limit resistance – avoid overuse of antibiotics, avoid broad-spectrum antibiotics, and complete courses of antibiotics when taken. It may also become necessary at some point to retire specific antibiotics for a number of years to allow resistance to wane over time.

Developing new antibiotics that work through entirely new mechanisms would also be welcome, but then it is only a matter of time before resistance develops to those new antibiotics. What is really needed is entirely new approaches to bacterial infection.

One emerging technology may be a significant new weapon is our war against bacteria – PPMOs, or Peptide phosphorodiamidate morpholino oligomers. PPMOs are synthetic DNA strands that bind to cRNA because they have the complementary, or antisense, pattern of base-pairs. They are therefore like a lock and key, and will specifically bind together.

PPMOs can be created to match RNA strands of specific bacterial genes – so they can be very specific, not just to bacteria, or even a specific species of bacteria, but to a specific gene. Once they bind they block the functioning of that RNA by blocking access to the cells machinery, called stearic hindrance. In this way they block the expression of the targeted gene. Turn off the right gene, and you can stop the bacteria’s life cycle.

This technology is still developing, but already there are animal studies showing that PPMOs have activity against bacteria and enhance survival from bacterial infections. They still need to be tested in humans.

PPMOs are also useful for more than bacterial infections. They can be targeted against genetic diseases, where the mutant gene produces an abnormal protein that causes or worsens the disease. The expression of the abnormal gene can be blocked by a targeted PPMO.

Unfortunately, there is already evidence that bacteria can develop resistance to PPMOs by evolving mutations. However, with PPMOs we can simply adjust the PPMO sequence to match the mutation.

It remains to be seen how powerful PPMOs will be in our ongoing fight against pathogenic bacteria. It does look like they have the potential to be a significant new weapon. There is not likely to be a single solution to the problem of bacterial resistance. Rather we will likely need as many different strategies as possible to keep one step ahead of rapidly evolving bacteria.

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