Is there such a thing as an “evolution-proof” drug? (part the third)

A claim that scientists need to quit making:

I’ve written about these types of claims before. The first one–a claim that antimicrobial peptides were essentially “resistance proof,” was proven to be embarrassingly wrong in a laboratory test. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.

A very similar claim made the rounds in 2014, and the newest one is out today–a report of a “super vancomycin” that, as noted above, could be used “without fear of resistance emerging.” (The title of the article literally claims “‘Magical’ antibiotic brings fresh hope to battle against drug resistance”, another claim made in addition to the “no resistance” one in the Scripps press release by senior author Dale Boger). This one claims that, because the modified vancomycin uses 3 different ways to kill the bacteria, “Organisms just can’t simultaneously work to find a way around three independent mechanisms of action. Even if they found a solution to one of those, the organisms would still be killed by the other two.”

A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.

Within the paper itself, the limitations are much more clearly laid out. Discussing usage of the antibiotic, the authors note of these conventional semisynthetic vancomycin analogs:

“However, their use against vancomycin-resistant bacteria (e.g., VRE and VRSA), where they are less potent and where only a single and less durable mechanism of action remains operative, likely would more rapidly raise resistance, not only compromising its future use but also, potentially transferring that resistance to other organisms (e.g., MRSA).”

So as they acknowledge, not really so resistance-proof at all–only if they’re used under perfect conditions and without any vancomycin resistance genes already present. What are the odds of that once this drug is released? (Spoiler alert: very low).

Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.

Part of this post previously published here and here.

Is there such a thing as an “evolution-proof” drug?

Eleven years ago, two scientists made a bet. One scientist wagered that a new type of antimicrobial agent, called antimicrobial peptides, would not elicit resistance from bacterial populations which were treated with the drugs. Antimicrobial peptides are short proteins (typically 15-50 amino acids in length) that are often positively charged. They are also a part of our body’s own innate immune system, and present in other species from bacteria to plants. It is thought that these peptides work primarily by disrupting the integrity of the bacterial cell, often by poking holes in them. Sometimes they work with the host to ramp up the immune response and overwhelm the invading microbe. Because the peptides are frequently targeted at the bacterial cell wall structure, it was thought that resistance to these drugs would require a fundamental change in membrane structure, making it an exceedingly rare event. Therefore, these antimicrobial peptides might make an excellent weapon in the fight against multiply drug-resistant bacteria.

Additionally, the remarkable diversity of these peptides, combined with the presence of multiple types of peptides with different mechanisms of action present at the infection site, rendered unlikely the evolution of resistance to these molecules (or so some reasoning went). However, evolutionary biologists have pointed out that therapeutic use of these peptides would differ from natural exposure: concentration would be significantly higher, and a larger number of microbes would be exposed. Additionally, resistance to these peptides has been detailed in a few instances. For example, resistance to antimicrobial peptides has been shown to be essential for virulence in Staphylococcus aureus and Salmonella species, but we didn’t *witness* that resistance develop–therefore, it might simply be that those species have physiological properties that render them naturally resistant to many of these peptides, and were never susceptible in the first place.

The doubter of resistance, and the bet instigator, was Michael Zasloff of Georgetown University, who wrote in a 2002 review of antimicrobial peptides:

Studies both in the laboratory and in the clinic confirm that emergence of resistance against antimicrobial peptides is less probable than observed for conventional antibiotics, and provides the impetus to develop antimicrobial peptides, both natural and laboratory conceived, into therapeutically useful agents.

Certainly in the short term, resistance may be unlikely to evolve for reasons described above. However, if these peptides are used over an extended period of time, could the mutations necessary to confer resistance accumulate? This was the question asked in a new study by Dr. Zasloff along with colleagues Gabriel Perron and Graham Bell. Following publication of his 2002 paper where he called evolution of resistance to these peptides “improbable,” Bell challenged Zasloff to test this theory. Zasloff took him up on the offer, and they published their results in Proceedings of the Royal Society

The result?

Zasloff had egg on his face. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.

Well, everything old is new again. A very similar claim has been making the rounds recently, originating from the press release for a new paper claiming to have found bacteria’s “Achilles’ heel,” advancing the claim that “Because new drugs will not need to enter the bacteria itself, we hope that the bacteria will not be able to develop drug resistance in future.”  A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.

Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.

Part of this post previously published here.

The human origins of “pig” Staph ST398

I recently gave a talk to a group here in Iowa City, emphasizing just how frequently we share microbes. It was a noontime talk over a nice lunch, and of course I discussed how basically we humans are hosts to all kinds of organisms, and analysis of our “extended microbiome” shows that we share not only with each other, but also with a large number of other species. We certainly do this with my particular organism of interest, Staphylococcus aureus. There are many reports in the literature showing where humans have apparently spread their strains of S. aureus to their pets (dogs, cats, hamsters)–and sometimes the pets have been nice enough to share it right back. My own research looks at S. aureus in pigs and the humans who care for them, and many studies have shown that a “pig” type of MRSA, dubbed sequence type 398 (ST398), can be transmitted from pig carriers to their human caretakers. The assumption has been that this is truly a “pig” strain, originating in swine, and has spread to humans (and other animals, including cattle, poultry, dogs and horses) from pig hosts, either directly or indirectly via contaminated meat products.

According to a new study (open access in mBio), it seems that there has been more sharing of ST398 than we’d realized. Led by Lance Price at TGEN (full disclosure–I’m a coauthor on the paper), his group analyzed 89 ST398 isolates from China, Europe, and North America, including isolates from humans and animals as well as both methicillin-susceptible and -resistant strains. Using whole genomic sequence typing, the evolutionary history of these isolates was reconstructed.

The findings throw the ST398 story a bit on its head. Instead of being a true pig strain, ST398 appears to have originated as a methicillin-susceptible human strain which was transferred into the pig population, picked up antibiotic resistance genes (including resistance to methicillin and tetracyclines), and then has been passed back to farmers as more resistant organisms. Some prophages were also gained or lost along the way, probably due to selection by host factors.

This also suggests that there is still likely a low level of “native human” ST398 circulating in people. There have been a few case reports of ST398 colonization and/or infection in people without any known livestock contact. Some of these have been resistant to methicillin and/or tetracycline, which are more frequently associated with livestock-adapted strains. Are these truly “human” strains which aren’t involved in livestock at all, or are these ST398 findings in people lacking livestock contact still due to some livestock exposure along the chain of transmission (farmer neighbors? Transmission via food?) We still don’t know, but carrying out more of this WGST will give us better targets in order to be able to differentiate true “human” ST398 strains from those that have been hanging out in animals, and then transmitted back to people.

Now, for long-time science blog readers, this story may sound a bit familiar. Indeed, it looks like ST398 has taken a very similar path to that of another animal-associated S. aureus strain, ST5. As Ed Yong described back in 2009, humans are also the ultimate origin of a “chicken” type of S. aureus ST5, which spread around the world in broiler chicken flocks. In Ed’s article, the first author of the chicken ST5 paper, Bethan Lowder, notes that the change in chicken farming from small farms to multinational corporations likely aided the spread of this organism–and the exact same thing has happened with pig farming.

One difference between the two is that ST5 causes disease in chickens, whereas ST398 seems to be a very rare cause of illness in pigs. This is likely one reason that ST398 in pigs went undetected until relatively recently–it’s simply not much of an economic issue for pig producers, whereas in chickens, S. aureus can cause several nasty diseases (such as bumblefoot and BCO) leading to animal loss (and thus, less money for the farmer).

So, where do we go from here? Clearly studies like this show the utility of using WGST to examine the evolution and spread of these strains. If you look at how spa types are distributed throughout the tree, you can see that those alone don’t tell you much about where the strain came from, or if it’s fully “human” or a pig-adapted lineage. Ideally, a set of simple markers could be found to distinguish ancestral human strains from livestock strains (as methicillin-sensitive ST398 can also be found in pigs, so methicillin resistance alone isn’t enough of an indicator that it’s a “pig” strain). We’ll be working on this in ST398 and other strains we see being shared between animals and humans, in order to better understand this generous sharing we’re doing amongst species.

Reference:

Lance B. Price, Marc Stegger, Henrik Hasman, Maliha Aziz, Jesper Larsen, Paal Skytt Andersen, Talima Pearson, Andrew E. Waters, Jeffrey T. Foster, James Schupp, John Gillece, Elizabeth Driebe, Cindy M. Liua, Burkhard Springer, Irena Zdovc, Antonio Battisti, Alessia Franco, Jacek Żmudzki, Stefan Schwarz, Patrick Butayej, Eric Jouy, Constanca Pomba, M. Concepción Porrero, Raymond Ruimy, Tara C. Smith, D. Ashley Robinson, J. Scott Weese, Carmen Sofia Arriola, Fangyou Yu, Frederic Laurent, Paul Keima,, Robert Skov, & Frank M. Aarestrup (2012). Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock mBio, 3 (1), 305-311 : 10.1128/mBio.00305-11

Margulis does it again

We all know of once-respected scientists who ended up going off the deep end, adhering to an unproven idea despite massive evidence to the contrary. Linus Pauling and his advocacy of megadoses of Vitamin C, or Peter Duesberg’s descent into HIV denial. It’s all the more disappointing when the one taking a dive is a woman, since there are, compared to men, relatively fewer female “big names” in the sciences. So when one goes from views that were, perhaps, outside of the mainstream (but later proven largely correct) to complete science denialism, it makes it all the more depressing. Even worse, mainstream popular science magazines like Scientific American (with this article by Peter Duesberg) and Discover (Duesberg again) give these ideas reputable press. And now Discover has done it again by giving “maverick” biologist Lynn Margulis a profile in their latest issue. More after the jump.
Continue reading “Margulis does it again”