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January 20, 2006

Antibiotic resistance rethought

Sorry for the posting lag, y'all.. I've been spending my Net time plumbing the depths of self-important "knowledge" that is Wikipedia. Truly the most kaleidoscopic venue for flame wars ever conceived. CE/AD anyone?

As most of you know, I'm an incorrigible contrarian, relentlessly thumbing my nose at pretentions of certainty wherever they lie. Since positions of consensus tend to be right more often than not, sometimes this behavior makes me look pretty silly. Nowhere has this been more true than in the field of evolution, where I had dalliances with the deniers. I'm back in the evolutionary fold now, as I would have always stayed if I had simply snorted in derision at the likes of Behe and Johnson. But to do so would have been worldview-cramping and, frankly, not as much fun. My odyssey through the world of evolution denial taught me much about the various flavors of creationism and Intelligent Design, some of which are -- let me be clear -- as scientifically absurd as their detractors have always maintained. Too bad the "defenders of science" often prefer rhetoric to science when it comes to making a defense; their public attacks on ID don't engage ID at all but rather a straw-man of ID, or the shadow government of ID, or skip ID wholesale and go straight to ad hominem.

Antibiotic resistance is a good example of this phenomenon, popular enough to grace the panels of Doonesbury and educate the kiddies on PBS. The argument goes like this: when we take antibiotics, we kill all the susceptible bacteria, but some individual bacteria in each population are not susceptible due to some mutation or genetic variation they have. By killing off the susceptible bacteria, we create an advantage for those bacteria that are resistant, so they will prosper. Eventually the vast majority of bacteria of that type that we encounter will be those which have the mutation or genetic variation that enables antibiotic resistance, and our antibiotic has become useless. This account of antibiotic resistance is, of course, a scientifically correct one. It directly refutes the (mostly young-earth) creationist argument that evolution is merely a negative force with no creative power, as well as tacitly disparaging the less-stringent "limits to change" conceit a la Phillip Johnson. The example is also good politics, in that it shows why we should care about defending evolution education: because if we ignore it, the bugs will eat us alive. So what's the problem?

The problem is that this story is a but not the scientifically correct account, and like evolution itself is much more nuanced than the point-scoring crowd will let on. Antibiotic resistance has all the thrill of a twisting-and-turning whodunit, at once fascinating and scary. You see, long before we were around to worry about bacteria, bacteria were worrying about each other. During those billions of years that they were on top of the pyramid, the bugs engaged in internecine chemical warfare (hmm, are we any different?). It was species against species in a world war, crafting diverse weapons of great potency. Countless antibiotics were made, and the lesser ones were usually lost forever as the genes of the defeated foe were obliterated. But sometimes an enemy's weapon still had use, so the victor kept the genes that coded for antibiotic synthesis and resistance, copied them, modified them, and handed them over to allies.

Fast forward to a few years ago. We had an antibiotic, vancomycin, isolated from the Actinomyces bacterium and well-nigh unbeatable. Antibiotic resistance had bit us in the past, but that was because there were options for mutation, it was thought. Vancomycin killed everything because it attacked the peptidoglycan coating of the bacteria, an all-encompassing packet that was essential to the bug's life. No mere point change of the genetic code, even the statistically unlikely handful of changes, could evolve resistance to this one because there were no options. A bacteria couldn't change the skin it's in, after all. But one day, we started seeing vancomycin-resistant enterococcus (VRE) in the hospitals. VRE is protected from vancomycin because it has altered peptidoglycan -- different skin. The peptidoglycan is altered by three genes vanH-vanA-vanX. Since the production of three genes ex nihilo would be every bit as miraculous as creationism, scientists rightly felt that they must have come from somewhere else. It turns out that they look very much like the genes from a strain of Actinomyces, which really shouldn't have surprised anyone, given that's where we found vancomycin in the first place. Why would the bacteria that makes an antibiotic want to kill itself in the process? The proposed path of the genes to Enterococcus looks like a terror network: from soil-dwelling Actinomyces on European farms to enterococci living in animals treated with the vancomycin derivative avoparcin, to a farmer with a stomach bug, to the hospitals in the U.S. somehow. Eventually somebody with VRE must have come in contact with Staphylococcus aureus and yet another superbug was born. Multi-drug-resistant Staph (MRSA) laughs at up to 18 antibiotics, and most of its defenses were acquired from some other species of bacteria.

Far from conforming to the just-so story for public consumption, most antibiotic resistance that human pathogens have developed in our lifetimes did not spring fully-formed out of the magical depths of Darwinian macroevolution. Sometimes a quick "point mutation" is enough to render an antibiotic impotent, but usually it's far more effective for a bacterium to grab somebody else's shield. And soil bacteria have quite the armamentarium, according to a new article in Science. This article and its accompanying perspective focus on the dark side of natural products: when you go searching for new antibiotics in nature, you'll likely find the defense is already in there too. Vanessa D'Costa and co-workers grabbed soil samples from a variety of environments, isolated 480 Streptomyces colonies, and subjected them to over a dozen antibiotics (including drugs in clinical trials and barely on the market). To their surprise,

Without exception, every strain in the library was found to be multi-drug resistant to seven or eight antibiotics on average, with two strains being resistant to 15 of 21 drugs (Fig. 1B). Reproducible resistance to most of the antibiotics, regardless of origin, was observed, and almost 200 different resistance profiles were seen (Fig. 1, A and C), exemplifying the immense genetic and phenotypic diversity of the collection of bacteria.

The perspective article by Alexander Tomasz dwells on past pathways of resistance (including the above example, vancomycin) and what we might do in the future to prevent it. Keeping cows from becoming superbug factories is a valuable protective step, but it's important to keep in mind that the study found antibiotic resistance in the soil "regardless of origin". I don't think it's right to assume that antibiotic resistance necessarily comes from a bacterium's being subjected to the new drug (how did soil from a Canadian forest end up exposed to gentamicin?). The soil simply has a lot of organisms in it, resistant to untold numbers of antibiotics, that can easily transfer their resistance genes to non-soil-dwellers. And they've been working at this game a lot longer than us.

Still, there's a bright side to it all: we have a golden opportunity to survey 3 billion years of chemical weaponry, analyze its weaknesses, and say "is this all you got?" I may be contrarian for saying so, but betcha it is. Exploring this reservoir of resistance gives us a chance to design really devastating antibiotics against which evolution will be no match.

Posted by The Greatness at January 20, 2006 09:32 AM