Bacteria acquire genes for resistance in three ways.
1. In spontaneous mutation, bacterial DNA may change spontaneously, as indicated by the starburst. Drug-resistant tuberculosis arises this way.
2. In a form of microbial sex called transformation, one bacterium may take up DNA from another. Penicillin-resistant gonorrhea (defined) results from transformation.
3. Most frightening, however, is resistance acquired from a small circle of DNA called a plasmid. Plasmids can flit between bacteria of various types -- they generally must be touching -- and carry multiple resistance. In 1968, 12,500 Guatemalans died in an epidemic of Shigella diarrhea, caused by a microbe harboring a plasmid that conferred resistances to four antibiotics!
But bacteria do something much more clever than just mutating. That's chancy, so bacteria prefer to share biochemical secrets -- resistance genes -- that enable them to resist or destroy antibiotics.
This diabolical bartering can occur in a couple of ways.
1. Some bacteria share plasmids -- small chunks of DNA, like mini-chromosomes -- that exist outside the main chromosomes. This sharing can leap broad divisions in bacterial phylogeny (defined). It's almost as if a cow could lend a crow a gene and teach it to grow teeth.
2. Gene cassettes are genes that can be spliced in the chromosomes (defined). While the mechanism is kind of complex, it can be compared to an expedition to a shopping mall, Davies says. Genes called integrons code for enzymes called integrases that can splice those cassettes into chromosomes or other genetic material where they become functional. That makes the integrons function something like a shopping cart, Davies says.
If bacteria can obtain resistance merely by accepting gene cassettes, then, like shoppers in a video store who aren't sure if they've seen their first selection, bacteria can pick up several cassettes and obtain resistance to several antibiotics. Furthermore, says microbiologist Abigail Salyers of the University of Illinois, "Bacteria also integrate resistance to disinfectants or to pollutants in these clusters. Thus disinfectant use or pollution can select for antibiotic resistance, which could be exactly what Merri Moken was finding back at the start of our story.
From the human point of view, the problem with this kind of resistance is its permanence. Once lodged inside the chromosome or plasmid, these resistance genes are distributed as normal genes to all daughter (defined) cells. "Origin and Interstate Spread..." in the bibliography gives a detailed picture of how a deadly bug that causes tuberculosis gained resistance to many antibiotics.
Mechanisms
So far, we've talked generally about resistance without painting a good picture of how it works. And here we're in for yet another surprise, yet more evidence of what might be called the microbial mind. It turns out that antibiotic resistance is part of a larger picture of the way microbes defend themselves against chemical threats in their environment.
It seems that these defense mechanisms are strangely similar across many kinds of organisms -- and many threats. "The issue of resistance is converging from the human infectious disease and agricultural angles," says plant pathologist Jo Handelsman, "whether the microbe is trying to protect itself against antibiotics, fungicides, insecticides, herbicides, even antiviral agents." Handelsman, who studies the interaction of fungi and bacteria at the University of Wisconsin-Madison, points to more similarities. "At the molecular level, there are only a few mechanisms of resistance: change the target molecule, inactivate or decompose the drug or pesticide, sequester (defined) the drug or pesticide, or keep it out of the cell" to begin with.
Let me see your sources
All in all, it makes sense that microbes would have defenses. After all, during their billions of years on the planet, they've overcome countless chemical hazards. But what is the source of the antibiotic resistance genes in the first place?
Probably the organisms that originally produced the antibiotics.
While this might sound odd, it's logical. Assume that I, a lowly bacterium, make some kind of chemical that, say, destroys bacterial cell walls. Wouldn't I need some kind of chemical defense against what kids sometime call "my own medicine?"
This supposition is not only logical, it may even be true, says Davies. "We find resistance genes in the streptomycetes (bacteria that produce many antibiotics) that have exactly the same biochemical function as the resistance genes" in samples from hospital patients. And since the gene sequences are similar -- but not identical -- it's tempting to think that the genes jumped between species, although Davies admits "we can't yet prove it."
Jumping genes
Salyers, who studies this process of gene jumping between species, says bacteria have many tricks for moving resistance genes. For one thing, they seem to be able to cause other bacteria to start genetic swap meets: When a DNA resistance plasmid released by a bacterium is accepted by another bacterium, the recipient may be stimulated to release its own plasmid, a process called retrotransfer. "This transfer capability gives bacteria the ability to sample DNA from other bacteria," Salyers says. To her, the relationship represents a new form of symbiosis (defined).
As if this prospect of bacteria ganging up to defeat antibiotics were not alarming enough, recognize that this generosity extends beyond members of their own species, Salyers says. "Just about any bacterium can get genes from just about any other bacterium."
What is the evidence for this movement? Scientists are finding distantly related bacteria with resistance genes whose DNA sequences (defined) are 95 to 99 percent identical. Although it's extremely improbable by chance alone, it's a strong suggestion -- but not proof -- that the genes have a common origin.
But don't forget that the bacterial anti-antibiotic toolkit also includes multiple mutations, which could explain what's happened in New York City, where a
deadly drug-resistant tuberculosis has been on the rampage.
