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— Photo: A. ROY CHOWDHURY

Bacteria busters: We can now expect a vigorous search for such potentiator molecules which are specific to the invader.

Without some of them, for example the bacilli in our intestines, we would not be able to digest some of the food we eat and drink.

Remove them from the body and we suffer indigestion and weaken. The relation between these microbes and us is symbiosis at the most personal level. To think of them as unpleasant slum-dwellers within us is to do them injustice.

Why then are we so concerned about infection? Because external invasion disturbs this cosy mutual coexistence, and leads to illness.

The very word infection comes from the Latin root for tainting, staining and thus harming. As Dr. Lewis Thomas writes in his ‘The Lives of A Cell,’ most bacteria are harmful to us only when they make toxins, which is when they are harmed or diseased.

This could happen when they accidentally find themselves in an alien environment, one they are not used to or comfortable in.

In an effort to accommodate to the new environment, they trigger biochemical reactions that suit them but which we, accidental hosts they have run into, find unacceptable.

We in turn mount a barrage of defence reactions to rid our body of the unwelcome guest. And if we cannot do it from within, we take drugs that aim to kill the invading germs.

These are the antibiotics such as ampicillin, ciprofloxacin or erythromycin. While most of the infecting bacteria are killed by these, a few freak ones survive the onslaught and remain in the body.

They are freaks because their genetic make-up is just a bit different from the rest, and it is this difference in their genes that has helped them withstand the effect of the drug.

And since bacteria reproduce not in years but in minutes, the body is challenged within a few hours by billions of these drug-resistant strains of the bacteria.

It is thus a battle of wits between the drug researcher and the fast-evolving microbe. It has time and numbers working for it. This double whammy makes microbes let their freaks and genetic mutants colonise any place — be it humans and animals, plants, even the Arctic ice or the boiling cauldron of natural geysers.

Darwin wrote of life forms coping with the environment and the survival of the ones fittest to do so.

We see Darwin in action here. The drug researcher has to understand the biology of the bug and devise new molecules that target such steps in its life cycle that would stop it dead.

At the same time, he should ensure that the drug does no harm to us and to the symbiotic bacteria within us — no easy task.

No wonder drug companies spend millions in this effort, against adversaries whose calendar allows genetic freaks evolve in time, selectively grow and flourish against many odds.

Hence the need for super-drugs against these super-bugs. The current family of antibacterial drugs comes in three kinds.

The ciprofloxacin class stops the DNA of the bacteria from replicating; as a result, future generations are eradicated.

The chloramphenicol type stops the bacteria from making proteins, the workhorse molecules in their cells that help them metabolise and live.

The third type is the penicillin group of drugs, which halt the construction of the cell walls of the microbe; without a wall the bacterium crumbles to death. And yet, mutant bacteria with gene changes that allow them to bypass or resist the action of these drugs survive and propagate.

How would it be, if we devise a method that would prod the bacterium to kill itself — one that would involve a fundamental step that does not care about any of the biochemical pathways of replication, metabolism or growth?

One such step is to simply burn the bug to death. But it will have to be controlled burning at ordinary temperature, called metabolic oxidation. And it would have to be done by the bacterium itself, namely self-immolation.

This way, the body of the human host and its endogenous symbionts would not be harmed — no collateral damage.

Such a step has indeed been discovered, and not with any new drug but by the existing molecules such as the floxacin and the ampicillin classes of drugs.

Professor James Collins and his colleagues at the Boston University School of Medicine have unravelled a new and additional effect that these drugs have on bacteria, which was not known until now.

Writing in the September 7, 2007 issue of the journal Cell, they show that these drugs tamper with the fundamental biochemistry of bacteria, namely the glycolytic cycle, which is the starting step in the digestion of food. As they tamper this cycle, they release considerable amount of positively charged iron atoms, which produces the ‘flame’ called hydroxyl radicals.

These radicals, as the Professor’s student Michael Kohanski put it: “will damage DNA, proteins, lipids in the membrane, pretty much anything. They are equal opportunity damagers.” They literally burn the bacterium to death.

What is nice is that this hidden pathway to bacterial self-immolation is prompted by already discovered and widely used bacteriocides.

As Collins points out, if we also add to them a second substance that will weaken the microbe’s ability to defend and repair the damage, we can potentiate or enhance the lethality of these drugs.

For example, bacteria use a protein called RecA, which helps repair DNA damage. A molecule that knocks out RecA action would be a good potentiator.

Further, since these drugs are specific to the invader and do not harm the helpful colonisers or our body itself, we are on safe grounds.

We can now look forward to some vigorous activity in the search for such potentiator molecules.

This has been already started by companies such as Cellicon Biotechnologies, Inc., a start-up company that Collins has co-founded, which is supported by the venture capital firm Pure Tech Ventures.

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