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Another Icon of Evolution Bites the Dust – Antibiotic Resistance

Molecular Mechanisms of Antibacterial Multidrug Resistance

Cell Magazine 22 March 2007

Michael N. Alekshun and Stuart B. Levy

Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA

Center for Adaptation Genetics and Drug Resistance, Department of Molecular Biology & Microbiology and Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA

Available online 22 March 2007

My emphasis.

Treatment of infections is compromised worldwide by the emergence of bacteria that are resistant to multiple antibiotics. Although classically attributed to chromosomal mutations, resistance is most commonly associated with extrachromosomal elements acquired from other bacteria in the environment. These include different types of mobile DNA segments, such as plasmids, transposons, and integrons. However, intrinsic mechanisms not commonly specified by mobile elements—such as efflux pumps that expel multiple kinds of antibiotics—are now recognized as major contributors to multidrug resistance in bacteria. Once established, multidrug-resistant organisms persist and spread worldwide, causing clinical failures in the treatment of infections and public health crises.

“There is probably no chemotherapeutic drug to which in suitable circumstances the bacteria cannot react by in some way acquiring ‘fastness’ [resistance].”

—Alexander Fleming, 1946

Efforts aimed at identifying new antibiotics were once a top research and development priority among pharmaceutical companies. The potent broad spectrum drugs that emerged from these endeavors provided extraordinary clinical efficacy. Success, however, has been compromised. We are now faced with a long list of microbes that have found ways to circumvent different structural classes of drugs and are no longer susceptible to most, if not all, therapeutic regimens.

The means that microbes use to evade antibiotics certainly predate and outnumber the therapeutic interventions themselves. In a recent collection of soil-dwelling Streptomyces (the producers of many clinical therapeutic agents), every organism was multidrug resistant. Most were resistant to at least seven different antibiotics, and the phenotype of some included resistance to 15–21 different drugs (D’Costa et al., 2006). Moreover, many isolates were resistant to daptomycin, quinupristin-dalfopristin, and telithromycin—all drugs approved by the United States Food and Drug Administration (FDA) within the last decade—as well as purely synthetic agents such as ciprofloxacin. These data not only suggest that our surroundings can act as a reservoir for new (and old) resistance mechanisms, but that the drugs we use to treat infectious diseases have long-lasting effects outside of the hospital. Many antimicrobial molecules exist for millennia stably within the environment (Cook et al., 1989), where they select and promote growth of resistant strains.

Resistance to single antibiotics became prominent in organisms that encountered the first commercially produced antibiotics. The most notable example is resistance to penicillin among staphylococci, specified by an enzyme (penicillinase) that degraded the antibiotic (Barber, 1947). Over the years, continued selective pressure by different drugs has resulted in organisms bearing additional kinds of resistance mechanisms that led to multidrug resistance (MDR)—novel penicillin-binding proteins (PBPs), enzymatic mechanisms of drug modification, mutated drug targets, enhanced efflux pump expression, and altered membrane permeability. Some of the most problematic MDR organisms that are encountered currently include Pseudomonas aeruginosa (another microbe of soil origin), Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae bearing extended-spectrum â-lactamases (ESBL), vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant MRSA, and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Table 1). Some like methicillin-resistant S. aureus couple MDR with exceptional virulence capabilities (Miller et al., 2005). Others, including some strains of P. aeruginosa, A. baumannii, and K. pneumoniae, manage to evade every drug within the physician’s arsenal (Levin et al., 1999).

The rest of the article is at the Cell Magazine link and requires a subscription.

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14 Responses to Another Icon of Evolution Bites the Dust – Antibiotic Resistance

  1. It was my impression that the take-home message from evolutionary biology regarding antibiotics was that we shouldn’t provide *environments* conducive to allowing those bacteria with resistance to proliferate. That is, we shouldn’t be dispensing antibiotics like candy because this allows the overall population of resistant bacteria to increase in number. The issue of *where* the source of the resistance variant/mutant came from, and whether it predated exposure to the antibiotic is interesting, but does not make or break the relevance of evolution here (as in the broad sense that I understand it). Natural selection is understood to act on both de novo mutations and existing variation in the population (or possibly transferred in laterally from another species).

    I think once again we’re stuck on the issue of whether or not evolution positively “constructed” something or created new information. In this case the something is/are the molecular mechanisms associated with the antibiotic resistance. Yet suppose this resistance was just a byproduct of some other biochemical pathway variation in species Y or individual X. Only the context of antibiotics makes it a meaningful, positive, achievement. (positive for the bacteria, that is, certainly not for us). Admittedly this is not–in my mind, at least–a very compelling case for the creative capacity of evolution, but I think it does give a hint of how even old bio-material/information can be reinterpreted and take on a different meaning in a novel environmental context. Unless you think that the resistance mechanism was intended for that express purpose (resisting antibiotics) from the initial design stage. .I’m tempted to say that I wouldn’t expect anyone to take that particularly position. Yet someone will no doubt prove me mistaken.

  2. It was my impression that the take-home message from evolutionary biology regarding antibiotics was that we just don’t know that much about it but we are trying to learn more and that thinking of antibiotic resistance in terms of Common Descent is a fool’s errand.

  3. great ape

    I think it’s pretty darn relevant to evolution that the means of antibiotic resistance didn’t evolve recently but were there all along. Changing allele frequency is a far different thing than creating a new allele.

    Experiments were purported to have “proven” that antibiotic resistance evolves de novo. Talkorigins makes this claim in multiple places. Therein lies the dead icon.

  4. great_ape is correct that antibiotic resistance does not make or break the relevance of evolution and has some good thoughts along those lines. However, it is difficult to see how this can be a “take home message of evolutionary biology,” as evolution appears more and more to have nothing to do with it. One can certainly appreciate antibiotic resistance and take measures to deal with it without buying into an evolutionary history or evolutionary explanation for the phenomenon in question. As is often the case, there is an observation about physical reality, and then there is the historical/explanatory gloss that is painted onto that observation. The latter is, disappointingly, regularly superfluous.

    Further, antibiotic resistance is often touted as an example of “evolution,” when in fact it teaches us absolutely nothing about macroevolution, and, as Dave points out, probably is not even a decent example of microevolution, as commonly understood.

  5. “Changing allele frequency is a far different thing than creating a new allele.” –ds

    Certainly, but then we have to ask where that initial variation came from. What produced the biological feature that conferred resistance?
    If it arose de-novo *at some point* in the past via nonintelligent means, then it does not bother me so much that it did not arise in “real-time” on demand. As long as it can arise de novo from nonintelligent means, I am content that it can and does happen in principle; that suffices for evolution.

    As I see it, there are only a few possible answers to the question of where the resistance trait came from. 1)the variation allowing for resistance arose de novo by nonintelligent processes at *some* point in the past and was present and available in some individuals when antibiotics were applied 2)it was present at the beginning as a designed feature for the purpose of antibiotic resistance or 3)it was present at the beginning as a designed feature but was not designed for antibiotic resistance. It was, however, subsequently co-opted for resistance.

    Putting aside what has been claimed on talk origins (I haven’t read what they say there) all evolution ever requires is that some version of #1 be true. In this instance, #2 is not very attractive. #3 is interesting, but if you open the door for #3, #1 doesn’t seem like so much of a stretch anymore.

    “One can certainly appreciate antibiotic resistance and take measures to deal with it without buying into an evolutionary history or evolutionary explanation for the phenomenon in question.” –eric anderson

    As I’ve said elsewhere, I extend the term evolution to include microevolution, which in turn includes population dynamics and the process of an allele sweeping through a population or subpopulation. In this sense, I understand evolution to be highly relevant to the process in question, and there is a wealth of evolutionary literature and models that may be of use in helping to formally understand the dynamics of resistance. Many here reserve the term “evolution” for the de novo construction of new complex features. Yet the processes that we can experimentally observe are, as you’re well aware, of a far more modest nature. Yet I understand these modest changes as related to the larger, more dramatic changes, so I envision evolution as a whole spectrum of phenomenon, from allele frequency dynamics to the more difficult to imagine constructive feats.

  6. Eric Anderson is extremely bright, insightful, and extraordinarily articulate. I encourage UD readers to visit:

    http://www.evolutiondebate.info/

  7. Antibiotic resistance is a huge icon of evolution. It is the icon that is usually trotted out to show the practical application of evolution in medical science. Am I the only one who has heard numerous jokes and put-downs about those who don’t believe in evolution not treating for antibiotic resistant bacteria?

    If you have been living in a cave and haven’t then follow this link.

    http://www.doonesbury.com/stri.....e=20060702

    It is funny, but not for the reason it tries to be.

  8. I think this is significant. Antibiotic resistance is THE icon, IMHO. At least, it’s the one that is always used to “prove” the “fact” of Darwinian evolution in a pinch. If we take the RM out and just leave the NS, is that really a good example of NDE? Just more evidence that we don’t know as much as we think we do.

  9. Shaner74, I fully agree with your summary of the above dialog, “If we take the RM out and just leave the NS, is that really a good example of NDE?”

    As it is becoming apparent that there is no scientific evidence that the antibiotic resistance that we see has anything to do with RM, the view that antibiotic resistance is a crushed icon of evolution seems fully valid to me.

  10. “The means that microbes use to evade antibiotics certainly predate and outnumber the therapeutic interventions themselves.” –bolded text above

    I was pleasantly surprised to find that I have access to the article referenced above. It is an informative overview of the various mechanisms of antibiotic resistance exhibited by bacteria. Unfortunately, there was little indication of what, if anything, has been demonstrated as occurring de novo under laboratory settings; I will look into this further.

    Given how the article ends, though, I think what they meant by the text I’ve quoted above is that the basic *strategies* used to evade antibiotics are more numerous and older than antibiotic treatments themselves. The fact that they do not believe all *particular* instances of resistance mechanisms predate our antibiotic treatments is clear from the fact that they conclude the article by saying the following:
    “As we face this critical problem, we need to be aware of the fluidity of the microbial genome and the relative ease with which resistance can emerge by mutation or gene acquisition. Recognizing the potential for the emergence of resistance should garner newfound respect for the discovery of new agents so urgently needed to cure infectious diseases.”

    I take that to mean that they agree with the notion that de novo mutations can and do arise in the contemporary environment. In that light, I think they should have reconsidered the wording they used in the text quoted above.

  11. great_ape wrote:

    “As I’ve said elsewhere, I extend the term evolution to include microevolution, which in turn includes population dynamics and the process of an allele sweeping through a population or subpopulation. In this sense, I understand evolution to be highly relevant to the process in question . . .”

    This is not an unreasonable position, and you state it well. I believe we are still left with two important questions:

    First, what is the source of the information in the first instance? Given that there is no detailed evolutionary history for the mechanisms in question (and certainly not a history that plausibly operates without input from an intelligent agent), then the mechanisms and the current functions they perform cannot operate as evidence for the evolutionary story. Otherwise, we come periously close to the precipice of tautology.

    Second, it is precisely this plasticity in the term “evolution” (e.g., macroevolution, microevolution, population dynamics, changes in allele frequency, etc.) that tempts many proponents to claim that observations on one far end of the spectrum are evidence for conclusions at the other end of the spectrum. We ought to be suspicious of a use of the term “evolution” that is so broad as to virtually encompass “all things biological.” Once we get to that broad of a definition, it loses all explanatory power and, as a result, the term can be completely jetisoned from most discussions and analyses of biological systems with no loss.

    I believe you have some good insights and thoughts about the question of antibiotic resistance. As concerns this particular thread, however, I believe Dave’s point, if perhaps a bit zealously stated, stands, namely that antibiotic resistance on one end of the spectrum is not evidence for broad-scale macroevolution at the other end of the spectrum. Given that this icon still shows up in recent texbooks, I personally am pleased to see evidence that might hasten this icon’s demise.

  12. GilDodgen said:
    Eric Anderson is extremely bright, insightful, and extraordinarily articulate. I encourage UD readers to visit: http://www.evolutiondebate.info/

    Thanks for this link GilDodgen; and thanks Eric Anderson. I’m looking forward to reading the many articles posted here.

    I read on Eric’s site:

    I would like to see, however, an updated documentary that fleshes out the details of the cellular mechanisms only alluded to in UML.

    I second that. I will buy a dozen for family and friends. UML was my first exposure to ID, and I’ve been hungry for more ever since. Providing this sort of education and making this information more accessible is a great way to promote an understanding of ID among the general public, IMHO. People tend to respect their teachers.

    Many of the youtube video links posted here several weeks back give some outstanding examples – ATP synthase, protein synthesis, topoisomerases and DNA supercoiling. A closer look at the mechanics of the bacterial flagellum would be terrific (Is that a proton motor like ATP synthase?) A primer on the DNA code including the macro code aspects of histone binding; DNA to nucleosome to chromatin, etc, etc.

    *gasp* must…have…UML…the sequel!

  13. May be I could provide some insight in bacterial resistance from IT point of view. We can imagine bacteria as single instance of our own computer workstation. Actually you can map all the software on your disk in single string of bits. So what is resistance to drugs actually are similar mechanisms of antivirus programms. There is no big difference between antibiotics and computer viruses which both tend to destroy some parts of the cell (system). So antivirus programs acquire those “dns parts” to incorporate into it’s own DNS (write on the disk) so to gain resistance against these antybiotics. Ofcourse I imagine that celluar mechanisms are much much more complex and much more clever, but there is no evolution. There is design!

  14. great ape

    Actually I do agree that de novo mutations can arise to give bacteria resistance to antibiotics. But here’s the deal. These are neither passive or random mutations. Going back to the Scripps research first posted here 18 months ago showing that bacteria appear to crank up the mutation rate of certain genes in times of stress it becomes apparent that they aren’t just sitting around waiting for a happy mutation to make them immune to poisons but have active mechanisms that seek a cure when needed and when a cure is found they pass it on to other bacteria through horizontal gene transfer. In design engineering this is called the “shotgun” approach. You have a problem, you don’t know exactly what’s causing it or how to fix it, but prior experience with similar problems points you to a range of possible solutions one of which will probably work. So you start putting in potential fixes one after another until you find one that works. Another common expression for this is run it up the flagpole and see who salutes.

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