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Outsmarting superbugs’ countermoves to antibiotics

super bugs

With drug-resistant bacteria on the rise, even common infections that were easily controlled for decades — such as pneumonia or urinary tract infections — are proving trickier to treat with standard antibiotics. New drugs are desperately needed, but so are ways to maximize the effective lifespan of these drugs.

To accomplish that, researchers used software they developed to predict a constantly-evolving infectious bacterium’s countermoves to one of these new drugs ahead of time, before the drug is even tested on patients.

In the study the team used their program to identify the genetic changes that will allow methicillin-resistant Staphylococcus aureus, or MRSA, to develop resistance to a class of new experimental drugs that show promise against the deadly bug.

When the researchers treated live bacteria with the new drug, two of the genetic changes actually arose, just as their algorithm predicted.

“This gives us a window into the future to see what bacteria will do to evade drugs that we design before a drug is deployed,” said co-author Bruce Donald.

Developing pre-emptive strategies while the drugs are still in the design phase will give scientists a head start on the next line of compounds that will be effective despite the germ’s resistance mutations.

“If we can somehow predict how bacteria might respond to a particular drug ahead of time, we can change the drug, or plan for the next one, or rule out therapies that are unlikely to remain effective for long,” said Pablo Gainza-Cirauqui, who also co-authored the paper.

Because bacteria reproduce so rapidly — growing and dividing from one cell to two in less than an hour — drug-resistant bacteria are constantly evolving, and researchers have to constantly develop new ways to kill them.

Since the first antibacterial drugs were introduced in the 1940s, bacteria have evolved ways to resist every new antibiotic that has been developed — a process that has been accelerated by the use of antibiotics in livestock to help them gain weight, and in humans to treat viral infections that antibiotics are powerless to cure.

“My kids are now 15 and 13, and some of the antibiotics they were given when they were little aren’t given anymore because they aren’t as effective,” Donald said.

The percentage of infections caused by the bacterium Staphylococcus aureus that have proven resistant to treatment has risen steadily from just over 2 percent in 1975 and 29 percent in 1991 to more than 55 percent today — resulting in more than 11,000 deaths in the U.S. each year, a higher death toll than HIV.

“For some antibiotics, the first drug-resistant bacterial strains don’t appear for decades after the drug is introduced, and in others all it takes is one year,” Gainza-Cirauqui said.

Until now, scientists trying to predict the genetic changes that would enable a bacterium to evade a particular drug have had to look up possible mutations from “libraries” of resistance mutations that have been observed previously.

But this approach falls short when it comes to anticipating how bacteria will adapt to new drugs, where the microbes can’t be counted on to change in repeatable, predictable ways

“With a new drug, there is always the possibility that the organism will develop different mutations that had never been seen before. This is what really worries physicians,” Donald said.

To overcome this problem, a research team used a protein design algorithm they developed, called OSPREY, to identify DNA sequence changes in the bacteria that would enable the resulting protein to block the drug from binding, while still performing its normal work within the cell.

The team focused on a new class of experimental drugs that work by binding and inhibiting a bacterial enzyme called dihydrofolate reductase (DHFR), which plays an essential role in building DNA and other processes. The drugs, called propargyl-linked antifolates, show promise as a treatment for MRSA infections but have yet to be tested in humans.

“We wanted to find out what countermoves the bacteria are likely to employ against these novel compounds. Will they be the same old mutations we’ve seen before, or might the bacteria do new things instead?” Donald said.

From a ranked list of possible mutations, the researchers zeroed in on four tiny differences, known as single nucleotide polymorphisms, or SNPs, that would theoretically confer resistance. Though none of the mutations they identified had been reported previously, experiments with live bacteria in the lab showed their predictions were right.

When the scientists treated MRSA with the new drugs and sequenced the bacteria that survived, more than half of the surviving colonies carried the predicted mutation that conferred the greatest resistance — a tiny change that reduced the drugs’ effectiveness by 58-fold.

“The fact that we actually found the new predicted mutations in bacteria is very exciting,” Donald said.

The researchers are now using their algorithm to predict resistance mutations to other drugs designed to combat pathogens like E. coli and Enterococcus.

The model could also be expanded to anticipate a microbe’s response more than one move ahead, Donald said.

“We might even be able to coax a pathogen into developing mutations that enable it to evade one drug, but that then make it particularly susceptible to a second drug, like a one-two punch.”

Their computational approach could be especially useful for forecasting drug resistance mutations in other diseases, such as cancer, HIV and influenza, where raising resistant cells or strains in the lab is more difficult to do than with bacteria, the researchers say.

The software they developed, called OSPREY, is open-source and freely available for any researcher to use — this means if you click the link you can download a copy yourself (sounds like fun doesn’t it?).

Sources:
Reeve SM, Gainza P, Frey KM, Georgiev I, Donald BR, & Anderson AC (2014). Protein design algorithms predict viable resistance to an experimental antifolate. Proceedings of the National Academy of Sciences of the United States of America PMID: 25552560

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9 responses

  1. I’m wondering if anyone here has any experience with the phage technology being used in Eastern Europe principally Georgia? Do you think they will ever act as a replacement therapy or ‘class switch’ when the final antibiotic loses its struggle?

    January 4, 2015 at 3:28 pm

    • That is a brilliant question. The answer unfortunately isn’t simple as I am sure you know given what I’ve gathered from your blog.

      The main reason it isn’t approved for use in the US has to do with the fact that it is a living entity with chance for mutation and evolution.

      Personally when the stigma from genetics dies down — which as history has shown it eventually will — I think it very well could replace antibiotics altogether given the technique is a much more targeted approach and doesn’t rely on the brute force antibiotics use. Unfortunately right now we can’t even get over “GMO” foods, much less “GMO” bacteriophages.

      Keep in mind the US FDA is a huge stickler for proof more so than most countries and half of the choices they make are based on popular opinion which is quite frankly a shame.

      So short answer, yes it will eventually. But I also think it will not be for a long time.

      January 4, 2015 at 5:17 pm

      • Interesting and I agree with you in terms of the politics.. I think the West (more specifically America) will take a lot longer to warm up to the Russian/Eastern concept of phages and phage technology than maybe Western Europe. Though this might (and probably will) rapidly change when a phage is your last chance of beating an infection.

        My real question is do they actually work? Have their been any western led papers about their specificity / efficacy? Also as I far as i understand (and I’m very ignorant here) can you have a ‘broad spectrum’ phage. For example whenever any elderly patient comes in with delirium and raised white cells / crp, and a few crepitations on the chest and a positive urine dip most doctors would give Co-Amoxiclav. Nice, broad spectrum, will cover urinary and chest infection. By definition isn’t it impossible to have a ‘broad spectrum phage’ as each phage should have unique tropism for a certain bacteria? It is very interesting and I which i could do some research in the area / work in the field. Imagine getting to work with Fleming or Florey and Chain before antibiotics became big business!

        January 5, 2015 at 10:45 am

      • Ah very good question, does phage therapy actually work. Unfortunately the answer is sometimes, in the (relatively) scarce literature on the subject there has been about a 50% success rate for treating antibiotic resistant infections (Not too shabby considering it’s 100% failure rate with traditional antibiotics) however on the bright side that probably has more to do with the preparation and delivery than with the actual treatment.

        Most of the research has been done across the pond in the EU (and of course primarily Russia, unfortunately the studies are of questionable value) , however the journal of infectious diseases published some work done here in the US which showed high effectiveness: http://jid.oxfordjournals.org/content/201/2/264.long

        Keep in mind that the mutation and resistance issue still applies to phage therapy, but according to findings from this study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694056/ it shouldn’t be as large an issue as with antibiotics.

        Broad spectrum bacteriophage treatment would be possible with a mix of phages, however they would still have to be custom made for the specific person and problem so truthfully the answer is probably no and your correct in assuming that by definition it wouldn’t work.

        I agree getting in on the ground floor for research would be incredible, you would probably go down in history if you could find a way to rapidly and cheaply produce personalized treatments and frankly we aren’t too far away from being able to do that so it might as well be someone like you or me.

        Once the US and more of the EU comes on board with the idea we should see huge advancements thanks to the money that would get pumped into the projects.

        January 5, 2015 at 12:15 pm

  2. Very enlightening answer. I’m just gonna leave this here… with a nice false colour electron microscopy picture of what I assume is E.coli, Klebsiella, Salmonella or Clostridium. http://www.bbc.co.uk/news/health-30657486

    Maybe you could write an article about phages?

    January 7, 2015 at 12:10 pm

    • Awesome link, I love the bbc news. I should write something up on phages, that is a great suggestion. Thank you.

      January 7, 2015 at 4:51 pm

  3. katethekitcat

    Very interesting model – but predicting how a bacteria/virus will mutate so we can preemptively create new drugs is still relying on making more drugs that a bug can eventually mutate against as well. Seems like we’re still spending most of our time speeding up the arms race, rather than figuring out how to bow out all together.

    January 7, 2015 at 1:53 pm

    • Very good point, ultimately the trick will be finding a way to use our own biology to block viruses and bacteria instead, that would ideally circumvent (at least for a little longer) the mutation problem. By the way are you still in med school or are you done, your blog is a little ambiguous.

      January 7, 2015 at 1:57 pm

  4. Pingback: New antibiotic may help slow drug resistance | Lunatic Laboratories

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