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Where MRSA Came From

OK, everyone recognizes the problem that we face with drug-resistant bacteria. MRSA (methicillin-resistant Staphylococcus aureus) is the most well-known variety, and it’s bad news. Penicillin was introduced in the 1940s, and methicillin was brought to market in 1959, largely because so many infections were becoming resistant to penicillin by then. The first methicillin-resistant strains were noted in the early 1960s, which would seem to make the story pretty clear.

But it isn’t. This paper has gone back into the details, sequencing the genomes of many of the earliest available resistant isolates, freeze-dried since their collection. And they find that MRSA bacteria actually predate the introduction of methicillin. So does that mean that they aren’t a product of antibiotic use? Not at all – it’s just that the antibiotic that brought them on was penicillin, not methicillin. Here’s how that seems to have worked:

Penicillin resistance is largely due to beta-lactamase expression in bacteria, the well-known enzyme that cleaves the beta-lactam ring common to all such antibiotics. (Dosing along with a beta-lactamase inhibitor, such as clavulanic acid, is a widely used strategy that’s often still effective). Methicillin is not a substrate for the enzyme (it’s the dimethoxyaryl amide in its structure that does it). Beta-lactamase is encoded by the blaZ gene, but it turns out that even in the 1940s, an alternative resistance mechanism was spreading, too, the mec gene cassette. In that you find mecA, which codes for a penicillin-binding protein (PBP2a), and that’s the one that does the job against methicillin.

The sequencing work here supports some other phylogenetic analysis, suggesting that these genes transferred once into S. aureus at some point in the mid-1940s, almost certainly from some coagulase-negative staphylococci. Strains with the blaZ gene were outcompeting wild-type bacteria by then, under selection pressure from the widespread use of penicillin, and strains with both the mec and blaZ genes were starting to outcompete them in turn. So it appears to have been that same use of penicillin that prepared the way for methicillin resistance. It worked fine against the earlier resistant strains that had only beta-lactamase as a weapon, but by the time it was introduced, those weren’t the whole problem.

To make things worse, streptomycin resistance seems to have come in at almost the same time, from the same branch of the family. The paper concludes that:

It therefore appears that the first MRSA clone emerged, and developed resistance to two of the earliest antibiotics—streptomycin and penicillin—almost immediately after the S. aureus population would have been first exposed to them.

At the time of its discovery, the incidence of MRSA in the general population is likely to have been very low. This is demonstrated by the fact that screening of over 5000 samples at Public Health England yielded only three methicillin-resistant isolates. Therefore, it is likely that when methicillin was introduced to circumvent penicillin resistance in S. aureus, it did not select for emergence of MRSA at that time, but instead provided the selective pressure, which drove the nosocomial spread of a pre-existing variant, at a time when infection control measures in UK hospitals were limited.

This adds to the usual feeling that we get, looking back at the earlier use of antibiotics and wanting to yell at everyone “Don’t do that!” Too late now. The whole story is a festival of unintended consequences, which we’re living with now.

49 comments on “Where MRSA Came From”

  1. SP says:

    In some sense that’s just bad luck, right? Kind of reverse SAR- you might expect a protein that binds penicillin but a similar but yet to be invented analog, but there was no way for bacteria to “predict” ahead of time that this other analog would be a useful thing to block as well.

  2. Andy II says:

    Well, this is always a Monday morning QB stuff. And, this drug resistance is not only for antibiotics (bacteria or viruses) but for all the therapeutic areas, even biologics (host immune systems and target molecules). I don’t think we can get away from this cat-and-mouse game. We always seek a new class of molecules with new MOA or outside the box approaches with improving host immune system as we see I/O. One more piece of publication related to this topic. Forsberg publication in Science in 2012: http://www.sciencemag.org/news/2012/08/soil-may-be-source-drug-resistant-bacteria

  3. db says:

    The timing of all this interesting as well, historically. Imagine if these resistances had developed a decade or two earlier, such that the antibiotics of the day had been losing effectiveness just at the time they were badly needed–during the second World War. Would discovery of new antibiotics have kept up? Would it have been significantly harder to deal with battlefield infections, and what could the consequences have been?

    I’ll have to go do some reading on the topic–who had what antibiotics during the war, and how quickly were they put into service once discovered? Could a wartime footing have enabled rapid growth in the available antibiotics, or would the redirection of resources toward weaponry have limited what was available for drug R&D? Has anyone written on the topic of the impacts of the war on medicinal research?

    1. Isidore says:

      “The Demon Under the Microscope” is a good book on the topic.
      https://www.goodreads.com/book/show/184327.The_Demon_Under_the_Microscope

    2. Michal Matousek says:

      The Russians were using gauze pads soaked with bacteriophages. Look at http://www.immlab.com for modern bacteriophage research. Thanks to Dr. Pillich they may be the furthest along with an effective bacteriophage treatment for MRSA.

  4. Emjeff says:

    We are not going to stop evolution. Like the Red Queen, we will have to keep running to keep pace with the organisms we are trying to kill. The FDA needs to get of its duff and make antibiotic development profitable again. Right now there is not difference in the development pathway between a drug that will be used for decades ( e.g., an anti-diabetic agent) and a drug which will be taken for 10 days at the most ( antibiotics). This has to change.

    1. T. Dougherty says:

      @Emjeff “The FDA needs to get of its duff and make antibiotic development profitable again. ” It’s a bit more complicated than that. The FDA’s mission is not to make drugs profitable. They can help by speeding approvals, and they now have QIDP (Qualified Infectious Disease Product) which fast tracks the process. But there are really two issues: antibiotic profitability (business) and antibiotic discovery problems (technical). A rather comprehensive review of these issues was published last year by the Pew Foundation: the full report is available as a PDF at the bottom of this page: http://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap-for-antibiotic-discovery

      1. Emjeff says:

        Wrong. It’s not the speed of approvals that is the problem, it’s the ever- increasing regulatory burden on clinical drug development. There are far too many regulations where the number needed to prevent a problem is far too high. The FDA’s current obsession with metabolites is a good example- a onerous set of regulations put in place to solve something that was never an issue in the first place.

        1. T. Dougherty says:

          I am not disagreeing that the FDA regulatory burden had a role. But lessening the regulatory role will only solve part of the problem. The failure of antibiotic R&D programs to come up with new compounds to address resistance has been an issue as well. A lot of big pharma money & effort went into programs for two decades with not a lot to show for it. There are some novel structures moving toward the clinic (e.g., ETX-0914) and new members of existing classes (e.g., plazomicin).

          1. Andy II says:

            “There are some novel structures moving toward the clinic (e.g., ETX-0914) and new members of existing classes (e.g., plazomicin).”

            Well, ETX-0914 is for gonorrhea infection. One dose treatment. Ceftriaxone /azithromycin is still effective after >20 yrs though there is XDR N. gonorrhea emerging. Plazomicin is for CRE cUTI or HAP/VAP. It will very likely be saved for the last option.

        2. ScientistSailor says:

          Wrong. There are many challenges with developing new abx, regulatory burden is actually a minor point, relative to the others. Finding truly new MOS’s against resistant bacteria is incredibly difficult, due to very high doses required and high mutation frequency, etc. No matter what you do the FDA, those problems remain. There isn’t some back-log of great abx just waiting for approval…

    2. Jb says:

      Oh puhlease. If it weren’t for shady drug manufacturers submitting shite applications with either fraudulent data or pumping blatantly misleading conclusions then maybe the FDA wouldn’t have to be so strict. I have many friends who work for the FDA with outstanding science credentials and the stories of the utterly stupid science they have to sift through in new drug applications is truly shocking. In one app my friend saw the scientists were literally grinding up warts, putting them into pills and administering them to patients in a remote hospital in Eastern Europe. Magically they claimed that they achieved efficacy for preventing HPV infections.

  5. steve says:

    It’s not the use of antibiotics as drugs that’s the major driver; it’s the use of antibiotics in livestock (which constitutes about 90% of antibiotic use). The use was almost guaranteed to promote resistance as it was used at subtherapeutic doses to promote growth. Europe banned the practice in 2006 but FDA didn’t get around to banning it until this year. The existence of MRSA bacteria may have predated the introduction of methicillin (most likely because some other microbes secrete something similar) but you can thank awful agricultural practices for greatly accelerating the selection of antibiotic-resistant bacteria.

    1. Derek Lowe says:

      That certainly seems like it should be so, but last time that topic came up around here, it proved harder than I thought to find human infectious resistant strains that could be traced back to that. What’s the state of the literature on this?

      1. Calvin says:

        We’re still a bit light on this to say the least. There’s nothing definitive yet, but since bugs don’t care if they infect a cow versus a person, it stands to reason that resistance in one will lead to problems in the other. Granted the immune system might provide a little wiggle room and some studies I recall did show a different resistance pattern between species, but my hunch is that resistance in animals will lead to problems in man. Afterall, animal models of infection are pretty predictive because the same bugs are quite happy to infect and kill multiple species. Pew, Wellcome, NIH etc have started funding some basic research here to try to get a handle on this one and collect some data.

        1. steve says:

          According to CDC it’s a big problem. “Antibiotics are widely used in food-producing animals, and according to data published by FDA, there are more kilograms of antibiotics sold in the United States for food-producing animals than for people… This use contributes to the emergence of antibiotic-resistant bacteria in food-producing animals. Resistant bacteria in food-producing animals are of particular concern because these animals serve as carriers. Resistant bacteria can contaminate the foods that come from those animals, and people who consume these foods can develop antibiotic-resistant infections. Antibiotics must be used judiciously in humans and animals because both uses contribute to not only the emergence, but also the persistence and spread of antibiotic-resistant bacteria.” (pp.36-37)

          “Scientists around the world have provided strong evidence that antibiotic use in food-producing animals can harm public health … Because of the link between antibiotic use in food-producing animals and the occurrence of antibiotic-resistant infections in humans, antibiotics should be used in food-producing animals only under veterinary oversight and only to manage and treat infectious diseases, not to promote growth.” (p..37)

          https://www.cdc.gov/drugresistance/threat-report-2013/

          1. Cato says:

            From what I understand, only certain antibiotics are used in animal feed, mostly those deemed unsuitable for use in humans or are “old” generations (e.g. early b-lactams, tetracycline, virginiamycins), so perhaps the correlation is not as direct as supposed. But wouldn’t be surprised if some newer generations make it into animal feed too despite gov’t regulation

          2. Some idiot says:

            As a reply to Cato, the problem here is mechanism. If two very similar antibiotics, with the same mechanism of action are developed, and one is used only in humans and the other only in livestock, then when resistance occurs to one, then it will also confer resistance to the other. This is the real problem, even with the more stringent regulations in the EU. For that strategy to work, you would need to ban drugs in livestock with a certain mechanism of action, and the farming lobby (apart from others) will never let that happen. Unfortunately.

          3. Cato says:

            Agree on the MOA problem, although I would be interested to see studies on say how readily penicillin G use would drive resistance to carbapenems for example. It seems to me that there would be more to the story. But given there’s only a handful of validated MOA’s out there for antibiotics, it seems unlikely that (m)any would be left after that stringency. Really we just need new classes of antibiotics, but then again why not ask for the silver bullet why we’re at it

          4. Some idiot says:

            Agree completely. On all major points! New MOAs and/or new paradigms are urgently needed. Some of the work on completely different means of addressing an infection sound very interesting, particularly if they can come up with a treatment where the treatment itself does not select for resistance.

      2. Wile E. Coyote, Genius says:

        the other really big issue, that has no contribution from agriculture is the over-prescription of antibiotics for humans. Those that have a viral upper respiratory infection that are given “prophylactic” antibiotics or that the patient demands antibiotics for a non-bacterial disease. These patients then do not take the full course and quit after only a dose or two. This is also a significant contributor to antibiotic resistance that has nothing to do with cows, pigs, turkeys, or chickens.

        1. CR says:

          Not sure the “not taking the full dose of antibiotics is bad or leads to resistance” is correct.

          https://www.statnews.com/2017/02/09/antibiotics-resistance-superbugs/

      3. NJ Micro Guy says:

        The best supported link is between use of virginiamycin in animal feed and vancomycin resistant Enterococcus. Recently the spread of MCR-1 and colistin resistance has been linked to its use in animal feed in Asia.

  6. Barry says:

    Beta-lactams (like Vancomycin, and the glycopeptides, and a few others) interfere with the construction of the peptidoglycan bacterial wall. I.e. they attack the bacterium from the outside, and are not whollysubject to resistance via efflux pumps. (note however: https://www.ncbi.nlm.nih.gov/pubmed/19279676)
    Other antibiotics that have to act in the bacterial cytosol are often defeated by efflux pumps. The efflux pump that defeat one class of antibiotics may confer to resistance to other (structural, mechanistic) classes of antibiotics that the bacterium has never yet seen. And lateral gene transfer via plasmids has spread these pumps across pathogens, human, bovine, porcine, avian…

    1. Some idiot says:

      Resistance to the Vancomycin class has evolved by the substitution of a D-alanine with a D-lactate in the cell-wall precursor. Stuffs up the binding to Vancomycin, but doesn’t make a difference to the cell. Mechanism has been well established, and some ingenious methods have been used to pull some of it back, but still…

    2. NJBiologist says:

      Pedantic point: although vancomycin does interfere with cell wall construction, it is not even remotely a beta-lactam.

      1. barry says:

        Like I said, beta-lactams and vancomycin both interfere with construction of the cell wall. Nowhere did I imply or say that vancomycin is a beta-lactam. Maybe my command of English is deficient. Where did this idea arise?

        1. barry says:

          Ah, I see the problem. It is “like”. Vancomycin is not offered as an example of a beta-lactam. It shares with the beta-lactams a site of action outside the bacterial cytoplasm, and therefore an insensitivity to efflux-pumps.
          Chemistry without pictures is hard to communicate.

          1. NJBiologist says:

            100% agree about communication… that’s always been a struggle for me, too.

  7. MikeRobe says:

    Stop blaming Ag for using ancient antibiotics and causing antibiotic resistance and look closer to home. You are constantly bombarded with consumer based chemicals that equally can trigger bacteria into becoming resistant. Yet few papers and scientists venture into this realm- too controversial and it makes Public Health shills look weak and enfeebled, although they would be the perfect fodder for bacterial infection.

    The fact that ARGs (antibiotic resistance genes) are in the permafrost, glacial ice cores and entombed in rock predating man show how wrong the field is.

    The resistome is infinite, ARGS are everywhere, and some of us will die due to bacterial infections. That’s just the way life is.

    1. ScientistSailor says:

      Take a look at the recent emergence of the mcr1 gene. A plasmid-encoded colistin resistance mechanism that is a direct result of using colistin as a growth promoter in pig.

    2. Michael Robertson says:

      Yes ARGs are everywhere, and honestly any new antibiotic produced will have an existing ARG awaiting it somewhere in the environment. The risk is transfer of that ARG from some random soil bacterium or commensal into a pathogen. This doesn’t mean that it is wrong to discourage use of antimicrobials in agriculture, or that non-clinical antimicrobials should get a pass. Tetracycline, an old old drug, can still select for resistance mechanisms that block nth-generation tetracyclines like tigecycline.

      Over use in humans is also a problem, not simply because your current pathogen will gain resistance, but also because selection for resistance will increase your carriage (or gene copy number) of ARGs, making in more likely in the distant future that your next UTI or nosocomial infection will have a chance to pick up an ARG as well. In this way antimicrobial use in humans or ag is akin to smoking: each puff will lead to mutations and it’s a roll of the dice if those ever become malignant.

      As for smoking guns, here are one each from animal and produce:
      10.1371/journal.pone.0127190 MRSA pigs leads to MRSA farmers
      10.1098/rstb.2015.0460 Azole fungicides leads to azole-resistance aspergillosis

    3. steve says:

      Sorry, but fake news. The issue isn’t whether ARGs are everywhere, it’s that normally they’re kept in check by the majority of non-ARG microbes but we disturb that balance and select out the ARGs when we indiscriminately toss tons of antibiotics into the environment through agricultural uses. This has been abundantly proven so it’s not even worth arguing.

      1. Derek Lowe says:

        I’m getting close to asking for an informal ban on the term “fake news”. We can’t escape it outside of this blog, but I wouldn’t mind putting up a fence, if possible. There are other, less politically fraught, ways of saying the same thing. . .

      2. MikeRobe says:

        ARGs are not kept in check by anything, and the fact that they are everywhere is not fake news. Then you post a dumb paper on transmission of MRSA from animals to farm personnel?

        Sounds like you and the antibiotic resistance community are trying to stay relevant in the face of adversarial findings. You should all just disappear or become chemists so you can help solve the problem instead of just enhance it.

        1. steve says:

          Sorry for the use of “fake news” but there needs to be some sort of defense against abuse of science for political purposes, whether it be denying the effects of CO2 emissions on global climate change, attacking vaccines or excusing the dumping of antibiotics into the environment. Fortunately, groups like CDC (previous links) and USDA (hardly anti-agriculture but willing to admit when there’s a problem and do something to try and solve it https://www.usda.gov/sites/default/files/documents/usda-antimicrobial-resistance-action-plan.pdf) go where the science leads. Hopefully they won’t be gagged like the EPA but we’ll see.

          1. Pennpenn says:

            It’s not like the words “lie”, “false”, “propaganda” or any number of other great words for expressing deceit or error evaporated in the last year or so, so people don’t really have an excuse for thoughtlessly echoing the Orange One when something that challenges them comes along and needs to be dismissed.

            In this case you could have just as easily said “Sorry but that is false” and it would have been a lot more appropriate.

        2. ESIMS says:

          Kept in check by evolution!
          You waste energy if you make such enzymes and keep those huge gene clusters in your genome under environmental conditions when they are not required. As a result another organism out-competes you and you are being overgrown. Exposure to tons of AB changes the situation: Now you do have a dramatic selection advantage and you grow exponentially. Why do you think those organisms enrich in samples where there is selection pressure like at hospitals & farms?

          Shove a pUC plasmid into E. coli, skip the selection & see how your miniprep yield decreases (and after how many generation times its completely lost).

          1. NJBiologist says:

            Thank you, I wondered when someone would say this. It costs energy to make beta-lactamases; alternate (vanco-resistant) cell wall chemistries are slower to assemble; and efflux pumps generally make nutrient enrichment harder. All of these make non-resistant bugs better competitors–if there aren’t antibiotic selection pressures.

          2. barry says:

            alas, when actual pathogens have been studied, resistance often persists even when the evolutionary pressure (the inducing antibiotic) is absent:

            https://academic.oup.com/femsre/article/35/5/901/2680377/Persistence-of-antibiotic-resistance-in-bacterial

            “in a few of the evolved lineages, this monotonous relationship was broken and an increase in resistance was found to be associated with an increase in fitness at a late selection step (Komp Lindgren et al., 2005). A reversal of the expected fitness–resistance relationship was also noted in constructed strains of S. pneumoniae carrying one or two fluoroquinolone resistance mutations (Rozen et al., 2007).”

          3. NJBiologist says:

            Barry, that’s an interesting review–although I thought there were some empirical findings (Europe, post-ban) that suggested that resistant bugs actually did what was expected and became a smaller fraction of the population. I don’t have citations on the tip of my tongue, though, so I’m going to have to dig a bit.

  8. Cephgroup-MC705 says:

    It has been argued that FDA policy to reserve new antibiotics as second-line treatment so as to limit development of resistance to new agents, discourages investment in new antibiotics by limiting potential sales before patent expiration. See PBS Newshour segments from Thursday and Friday of last week for examples of this argument. Do folks with direct experience working in antimicrobial discovery agree with this view?

    1. Some idiot says:

      There was an excellent discussion of this point in a comment to this blog sometime in the last few months (time flies…!). Another related point (if I remember correctly) was that if a drug is to be tested in the clinic as a second-line treatment, the the logistics/ethics of doing Thorsen trials for s also very complicated. Again, would someone in the know like to comment/correct me?

    2. Barry says:

      On one side, a hypothetical, new antibiotic would be constrained in the U.S. by the FDA’s preference to hold it as a last-line defense against the scariest organisms. On the other side there’s the prospect of a pirate lab (traditionally in India) selling it OTC in violation of the patent. Between this Scylla and Charybdis, there’s the prospect that the innovator may not make back the Research and Development costs.

      1. greasypocket says:

        This is a problem with pharmaceutical development in general. China and all other developing countries will rip-off the original inventor in a heart beat. And yet US pharma companies still keep out-sourcing jobs to these countries which have no respect for international patents or IP. A ridiculous state of affairs.

  9. steve says:

    There are a number of reasons why the normal market doesn’t work for new generation antibiotics, such as the point made by Cephgroup-MC705. That’s why CarbX was formed (http://www.carb-x.org). You wouldn’t know it in the current ideological environment but government solutions sometimes are better than private industry for solving unmet needs.

  10. Jb says:

    Not a microbiologist. Why can’t we gentically engineer a staph bug using CRISPR with suicide genes that’s also much better at plasmid transfer in order to wipe out nasty MRSA drug resistant microbes?

    1. ScientistSailor says:

      @JB Interesing idea, but most likely the bug would just delete any non-essential gene that is detrimental to it’s own survival. Deletion or inactivating mutations occur with very high frequency (1x10e-6).

  11. Foodscience says:

    The reason antibiotics are/were continuously fed to farm animals is feed efficiency. So 100 lbs of corn will make 52lbs of chicken, instead of 50lbs without antibiotics. I don’t believe the mechanism has been elucidated; but it might be a similar thing to statins, LDL, and morbidity( how the LDL might be unrelated).

    It seems like the biggest issues with antibiotic resistance is is general hygiene(ex, properly showering before a surgery), not finishing a regimine, how prescribers act. Pathogenic bacteria will never go away, so we need to do what we can and save antibiotics until they’re necessary.

    Last point, the majority of antibacterial agents/classes have been found in nature. It seems likely there are some populations of common bacteria that are already tolerant to them.

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