21 December 2007

Creationist Resistance to Antibiotic Resistance, Part II

When last we left our story of evolution and antibiotic resistance, we looked at the importance of random mutation to the development of resistance. Now that we’ve addressed (at least in a small way) the origin of these resistance genes, we can take a look at their greater role in evolution.

Commenter Dan Gaston got us off to a great start on the last post, noting that lateral gene transfer is in fact a primary mechanism of bacterial evolution, even though it doesn’t explain the origin of the genes being transferred.

At the end of the day, evolution is about change, plain and simple. Creationists don’t seem to realize this, as evidenced by their second objection to resistance as evidence of evolution: “If resistance DOES result from random mutation, it doesn’t count as evolution, because there’s always a price to be paid for gaining resistance.”

This is the sort of approach taken by Michael F. Behe, who likens the development of resistance genes to “trench warfare” and genome degradation, rather than an “arms race” of increasing buildup. Like many things that Behe believes, this is baloney.

First of all, it misses the point of evolution, which (as I said before) is change. Whether or not these changes meet Behe’s mystical criteria for “increasing complexity” doesn’t matter. It’s still evolution.

But more importantly, it’s short-sighted. As we’ll see, evolution of resistance means more than just having a resistance gene.

ResearchBlogging.orgOne thing is true about the creationists’ claim: in the majority of cases, resistance comes with a cost. Antibiotics work by disrupting some normal process within the cell. Resistance genes can operate by two different mechanisms: they can either disrupt the normal cellular process so the antibiotic can’t target it anymore, or they can create new proteins that actively do something to inhibit the antibiotic (like export it or degrade it). The latter is typically a plasmid-bound resistance gene, the former more typical of chromosomal mutations. But in the absence of antibiotic, these resistance mechanisms tend to lead to decreased growth. Mutations that disrupt antibiotic activity also decrease the efficiency of the targeted cellular process; proteins synthesized from plasmid might have a side effect on normal cell function; even just copying an unused plasmid is a waste of energy. From am medical perspective, this suggests that when antibiotic resistance crops up, we can just take away the antibiotic for a little while and the antibiotic-sensitive bacteria will eventually outbreed the resistant bacteria, and we can start over.

Behe and other creationists quit there and call it a day. But the problem is that all these studies of the cost of resistance were performed in na├»ve bacteria. That is, one minute the bacteria didn’t have the resistance gene, the next minute they did, and we looked at the difference.

What would happen if we let the bacteria and their new resistance genes get accustomed to each other for a while? Evolution would predict that, in the absence of antibiotics, there would be pressure to ameliorate the cost of resistance through mutation. Either you get rid of the resistance gene causing the problem, or you keep the resistance gene but acquire new cost-compensatory mutations that reduce its side effects.

Several studies were performed to test that hypothesis. Richard Lenski published a great review article in 1998 covering several of them.[1] You can read it for yourself here [PDF]; I’ll do my best to summarize some of the major findings.

Cost-compensation of plasmid-bound resistance:

A strain of E. coli was transformed with a plasmid carrying resistance to the antibiotics tetracycline and chloramphenicol. For this generation of bacteria, the cells with the plasmid were slightly less fit than those without (in the absence of antibiotics).

The researchers then grew the plasmid-carrying bacteria for 500 generations (75 days) in a culture containing chloramphenicol, to make sure the cells didn’t just ditch the plasmid. They then took those bacteria out of the chloramphenicol and isolated a colony of cells without the plasmid. For this generation of bacteria, the cells with the plasmid were slightly more fit than those without!

Further study showed that it was the bacterial chromosome that had changed, not the plasmid. Over just five hundred generations, enough cost-compensatory mutations had accumulated on the bacterial genome to make the resistance plasmid a boon rather than a bane, even in the absence of antibiotic.

Cost-compensation of chromosomal resistance mutations:

Here, researchers started with mutations of rpsL, a gene that encodes part of the bacterial ribosome (a little blob that synthesizes protein), that result in streptomycin resistance in E. coli. Streptomycin is a type of antibiotic called an aminoglycoside; it binds to the ribosome, preventing protein synthesis and killing the cell. Certain rpsL mutations prevent streptomycin from binding to the ribosome, thus making the cell streptomycin-resistant. However, this change to the ribosome also slows the rate of peptide (protein) elongation.

The researchers grew streptomycin-resistant bacteria in the absence of streptomycin (since it’s on the chromosome, not a plasmid, they don’t have to worry about the gene just being lost), and after a mere 180 generations they found that the rate of peptide elongation was back up to what it had been in wild-type cells. What’s more, they found that the bacteria still had the mutation conferring streptomycin resistance. Rather than mutating back to wild-type, the cells had acquired cost-compensatory mutations elsewhere in the chromosome.

These two studies indicate that fighting antibiotic resistance would be a LOT harder than was previously thought. It isn’t as easy as just taking away the antibiotic and letting the resistant bacteria fade into obscurity. Rather than ditch their costly genes for resistance, the bacteria are evolving cost-compensatory mutations so they can have their cake and eat it, too.

Hm… multiple naturally-selected mutations leading to a benefit with little or no noticeable cost? Sounds like evolution to me.

PS - One final note on the matter of antibiotic resistance, via Greg Laden: apparently there is some hesitation on the part of biomedical journals to refer to the “evolution” of antibiotic resistance, preferring instead to use terms like “emergence.” Head over to Greg’s place to check it out.

[1] Lenski, R.E. (1998). Bacterial evolution and the cost of antibiotic resistance. International Microbiology, 1(4), 265-270.

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