All it takes is a few mutant microbes to cause trouble.
Antibiotic resistance is a growing problem. The pharmaceutical industry comes up with a killer antibiotic (no relation to a killer app) to do away with some killer bug or bacterial strain and everything seems hunky-dory (no relation to the Bowie album) -- thanks to that antibiotic, that killer bug is no longer so killer. But, as we have unfortunately found, that is not the end of the story. Eventually, if we keep using that same antibiotic, the bugs become resistant to it and start causing havoc all over again. The pharmaceutical folks have to head back to the lab to find a new killer antibiotic and the whole thing starts over again.
Examples of this sad tableau abound: notable are strains of Methicillin-resistant Staphylococcus aureus (MRSA), Group B streptococcus, and Streptococcus pneumoniae, to name but a few. The long and short of it? A seemingly endless war between man and bug.
To learn more about it, Henry Lee of Boston University and colleagues experimented on a strain of Escherichia coli (E. coli) bacteria. Their results, published last week in the journal Nature, paint a fascinating, some might say frightening picture of a few altruistic members of their bug community helping the whole group to survive under the onslaught of ever heavier doses of the antibiotic norfloxacin.
(In case you are curious, norfloxacin is used to treat urinary tract and prostate infections and can have some serious side effects including tendonitis and tendon rupture. Of course that's nothing compared to what they can do to bacteria, that is, until the bacteria develop resistance.)
The authors set out in their experiments to create a resistant strain of bacteria by, as I just mentioned, exposing a colony of E. coli to ever larger doses of norfloxacin. They began with 50 nanograms per milliliter on day one, then isolated the survivors and hit them with a higher dose, and isolated those survivors and repeated the whole thing for 10 days when the dose was up to 1,500 nanograms per milliliter.
At each stage in the experiment, Lee et al took small subsamples of the colony and analyzed their resistance to norfloxacin. They found something unexpected: most members of these subsamples were unable to withstand the concentration of norfloxacin that had been administered to the entire colony; the authors called these less resistant isolates or LRIs. By contrast they found a very small number of mutant individuals that were highly resistant to norfloxacin -- that is, their resistance was higher than the concentration of norfloxacin that had been administered. These the authors referred to as highly resistant isolates or HRIs.
The key to understanding what is going on? Indole production. Indole is an aromatic organic compound that E. coli produce to trigger cellular defense mechanisms that pump the antibiotic out of the cell before it can deliver its fatal blow; however, antibiotics can shut down indole production in E.coli.
The HRI in Lee et al's experiment were the small number of bacteria in their community that had mutated in such a way as to give them resistance to norfloxacin. Okay, that explains why the HRIs survived, but how, Lee et al wondered, did the LRIs survive.
To answer that question, Lee's team dosed the LRIs with norfloxacin by themselves and with a small cohort of HRIs mixed in. By themselves the LRIs perished, but with the HRIs the LRIs survived. It turns out that the HRIs already resistant to the antibiotic continue to produce indole which in turn provides a level of protection to the LRIs that they would not otherwise have. Moreover, the authors were able to show, using a laboratory-generated HRI that was unable to produce indole, that the production and sharing of the indole by the HRIs in their experiment came at a "fitness cost" to them -- that is, the production and sharing of indole limited their own growth while benefiting the whole community.
This type of altruistic behavior is similar to kin selection whereby organisms favor strategies that allow their kin (and by extension their own DNA) to survive even though there is a cost to the individual. We expect to see such kin selection in human communities, but not so much in communities of one-celled bugs. And I for one would prefer not to see it in bacterial communities bent on overcoming our antibiotic defenses and doing us in.
In the war between man and bug, the road will undoubtedly be long. Could it be that the outcome will depend on whether we or bugs are better able to share the load with our kin? And on we go.
Crossposted with www.thegreengrok.com.
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