Random Science Class #1: Antibiotics at the Crossroads...

There was a recent article in Nature called “Antibiotics at the Crossroads” (Nature 431: 899-902). Whilst the article hasn’t really said anything new to people within the antibiotic research community, it is good to see such a piece within the hallowed covers of Nature. As Nature is not a freely available journal, I’ll provide a summary....

Basically, it discusses some of the problems with the development of antibiotics in the modern, stock/money-driven pharmaceutical climate. You see, the big pharma are not interested in producing specialised antibiotics to many different bacteria, as there is no profit in it. It specialises in producing, and derivatising, currently existing classes of broad-spectrum antibiotics, which can be used for a variety of bacterial infections by the greatest number of people. This problem is compounded by the requirement for physicians to ration the amount of antibiotics prescribed in order to prevent resistance. So the profit margins of the pharma companies dwindle. No feedback equals no new research and development.

This is a big problem, because we need to start researching the next classes of antibiotics now, if they’re going to be ready for release when we really need them...and we will. It has already been demonstrated, in a number of trials, that simply removing the antibiotics does not result in the loss of the resistance phenotypes, i.e. the ability of a bacterial species to resist antibiotic. A phenomenon called “gene silencing” enables the genotype (i.e. the ability) to persist in the absence of selective pressure (i.e. the antibiotics). When the selective pressure is again applied, the silence is removed and resistance occurs.

We are talking about infectious diseases here, which are the second greatest killers in the developing world, and the third greatest killers in the developed world!

So the pharma companies make their money by selling their wares to the food industry, hence the pumping of livestock (pigs, cows, sheep, chicken) with “growth enhancing” antibiotics. Resistances developed within this economical biome invariably find their way into human populations, quickening the downfall of the drug and leading to once-treatable infections.

We can’t start and stop antibiotic research like a tap. I work within this field and I will use myself as an example. I am part of a number of groups researching possible targets for rational antibiotics design. We look at certain aspects of a multidrug resistant hospital pathogen that enable it to disseminate antibiotic resistant traits to other bacteria. By studying these processes we can understand what features need to be disabled. Similar research is being carried out by other research groups on other aspects of cell life cycle: to kill the cells, inhibit their growth, or reduce the pathogenicity (ability to cause disease).

The trouble is, most of us are funded by government research councils and not by pharma. When the money runs out, we will move on elsewhere – probably leaving the antibiotics research community – and our projects will sit idle. When pharma decides to renew funding, where will we be? We’ll not be available as experts in their fields anymore. Our research will be languishing in a freezer somewhere as we hadn’t enough money to finish the work or publish it (which is an expensive process).

So the aim at the moment is to persuade Pharma that there is an economical advantage to producing drugs – if only for the third world. At the moment they are still trying to focus their attention on long-term illnesses such as Tuberculosis, where a steady income of profit is made over a long period (as it takes some time to treat sufferers). This, of course, is no aid to those people dying of hospital acquired “superbugs” who can go from fit, to dead within two weeks! There are drugs out there, but they are used sparingly as resistance develops very quickly, and epidemic resistance is greatly feared.

The article goes on to suggest that what we need is a “not-for-profit” industry to develop such antibiotics. There are only really SIX classes of antibiotics that represent all of the antibiotics known. They target a fairly limited range of important cellular functions, and every “new” antibiotic, per se, is simply a derivatisation of the current class; a new chemical group here or there that changes the properties slightly and gets around the resistance mechanisms...but not for long. You see, there is a “dogma” of research in this area. The methods of identifying antibiotics are well defined. What is needed is a more rational approach. Think about the solution, not the problem. Design antibiotics to attack specific molecules. Get constructive!

The other problem is that (in the US) the FDA requires that new antibiotics be more efficacious (better) at killing their targeted bacteria than the current ones, without the question of resistance – or if this is addressed, it is often insufficiently so. You see, there may be an antibiotics out there at the moment that is fantastic at killing sensitive bacteria, but there may be resistance developing to it. So here comes anew antibiotic. It’s not quite as good at killing the cells. Well, into the trash can with it...but wait a second, there is NO resistance to it. Tough. In the bin with it. Surely using it would be better than nothing? The fact that it kills the cells just a little more slowly is surely compensated by the fact that it is more readily useful in situations where resistance is present? Bureaucracy! Money!

So for now, what happens is that drugs are used in combination therapy, i.e. cocktails of different classes of antibiotics. In these cases it would be highly unlikely that resistance could develop to all of the drugs being used at the same time. This is quite effective, and it is often all we have at the moment. All new antibiotics should be used in such a manner, to increase their shelf life.

There is so much to say about this. There is so much to describe about how many antibiotics act only on bacteria in a particular life-cycle and that bacteria may avoid entering that life-cycle for the period of the antibiotic treatment, hence persist.

Here is a funny excerpt from the article:

The History of Medicine

2000 BCE – Here, eat this root
ACE 1000 – That root is heathen. Here, say this prayer.
1850 – That prayer is superstition. Here, drink this potion.
1920 – That potion is snake oil. Here, swallow this pill.
1945 – That pill is ineffective. Here, take this Penicillin.
1955 – Oops...bugs mutated. Here, take this Tetracycline.
1960-1999 – 39 more “Oops”...Here, take this more powerful antibiotic.
2000 – The bugs have won! Here, eat this root.

All is not lost though. Sooner or later Pharma will realise the dilemma, and we will be waiting to make some money and solve a problem. There are plenty of chemicals out there that blast the crap out of bacteria, but the trouble is, they've not got to kill the patient – that’s the hard bit!