Wednesday, June 28, 2017

STAT Proves Not Resistant To Antibiotic Tropes

Tuesday's Boston Globe carried a piece originating from STAT news on an interesting natural product antibiotic, pleuromutilin.  A research group recently published a new total synthesis of this fungal terpene, an advance which promises to enable greater medicinal chemistry around the molecule.  That part is cool.  Unfortunately, when it gets to the biology of pleuromutilin the piece by Eric Boodman completely spits the bit, trotting out some horribly inaccurate tropes.

But first, a bit of reminder.  I am employed by a company searching for natural products from bacteria, with antibiotics one possible indication for those natural products.  Natural products: the final frontier.  Our five year (well, now continuing into year six) mission: to seek out new actinomycetes and bioactive compounds.  To boldly go where no sequencer has gone before!

So I could understand if someone thinks I'm just slagging the competition or a bit green with envy or such.  But I wish to convince you that is not the case.  Like I said, the chemistry is cool -- it's the biological reporting that's appalling.

I also get that a piece aimed at a general audience is going to snip some corners. Biology is full of nuance and exceptions, and trying to cover all those can bog down the story, particularly when aimed at non-specialists.  But this isn't a case of making some small errors; the errors are huge and significant.

There is one short paragraph of the article that succeeds in setting up the two fallacies that irritate me.  Later paragraphs expand and embellish these whoppers, but let's focus on their introduction.
What is most exciting about pleuromutilin, though, is that there was no documented resistance to either the animal or human antibiotics derived from it. That's because the substance throws a wrench into the fundamental protein-producing machinery of the bacteria.
Actually, I guess I could really score that as three fallacies.  The second sentence really has two fallacies for the price of one.  Here are the three

  1. There is no observed resistance in the field to pleuromutilin
  2. Pleuromutilin is unique in targeting translation
  3. Translation is so fundamental that bacteria can't mutate to generate resistance.
Okay, let's dissect these in order.  

If you are going to write about biomedicine, particularly for a site like STAT that is aiming for (and usually hitting) high standards, you really, really need to learn to do a simple PubMed query.  let's try "pleuromutilin AND resist*".  That yields 117 hits just now, but many of those are talking about other things.  But we have some candidate winners just at the top.  #3 is a review titled "Assessment of the Risk to Public Health due to Use of Antimicrobials in Pigs-An Example of Pleuromutilins in Denmark.".  Number 4 talks about isolates from Italy.  And many more.

So hogwash.  Really! That might be a good place to look for bacteria resistant to pleuromutilins. Many of the papers concern resistant isolates found in pigs from a variety of countries.

Targeting translation?  Well, that's hardly unique.  Indeed, that's how tetracyclines work.  And aminoglycosides such as streptomycin. And macrolides such as erythromycin. And lincomycin And numerous other antibiotic classes.  Note that these are natural products: nature loves to target the ribosome.  

Now let's get to that idea that translation, or the site specifically targeted by pleuromutilin, is somehow so fundamental bacteria can't evade it.  First question: how do the producers evade it?  Well, it is a fungal natural product, so not much of an issue (though mitochondria can be sensitive to antibiotics targeting bacteria, such may be the case with aminoglycosides).  Next, what is the spectrum of activity?  Not universal: there are definitely bugs which aren't bothered much by clinical doses of pleuromutilin.  So there must be some way for bacteria to evade it.

What that third claim ignores is that bacterial resistance to antibiotics can take many forms, with mutating the target just one of the tricks that can be deployed.  Antibiotics can be excluded from the cell or pumped out or bound to a sequestering protein.  Antibiotics can be modified or destroyed by enzymes.  

If we look through the literature from that search, we find multiple mechanisms at play.  There are, for example, plasmids which carry a protein which has a gene conferring resistance to multiple ribosome-targeting antibiotics.  The protein is a curious beast, related to ABC transporters.  Most ABC transporters are either importers or exporters; the CFTR protein mutated in cystic fibrosis is in this family as is the famous white mutation in Drosophila and also drug exporters important in bacterial resistance to certain antibiotics and cancer cell resistance to some chemotherapy compounds. But the protein yielding pleuromutilin resistance is in a funny subfamily that lacks transmembrane domains and appears to interact with the ribosome.  Particularly worrisome is that already multiple versions of this protein have been found in wild isolates.

What about those target mutations which the article suggests are impossible?  Nope, not impossible.  And they're all over the ribosome.  Ribosomal proteins L3(rplC) and the 23S ribosomal RNA (also reported from field strains; the abstract of the first I found is ambiguous and the article is behind a paywall).  And this has been seen in multiple bacterial species for both the 23S ribosomal RNA and rplC.  Selecting for a pleuromutilin resistant mutant has even been used to boost production of a different antibiotic (a fascinating and somewhat enigmatic process known as ribosome engineering). 

So is this just molecular nitpicking?  Complaining about deep details not suitable for lay audiences?  I would argue not.  The problem we as a species face with antibiotics is that we as a species have used them indiscriminately.  This has placed tremendous Darwinian pressure on bacteria, which have responded by becoming resistant.  To me, the "hey, we have an antibiotic which is resistance-proof" is both dumb biology and dangerous medically.  The last thing we need is something that might lead some people to think "don't worry -- the silver bullet is on its way".  If we are going to convince the public to be part of the good antibiotic stewardship equation, then we can't feed them falsehoods that undermine the urgency of changing our ways.

[2017-06-28]: Two morning after additions.  First, Eric Boodman tweeted he will be making corrections.  The article is behind the STAT+ paywall, so I may not be able to review them -- but it is great to see an journalist who responds positively to constructive criticism.

I'm really annoyed I didn't enumerate in the original post another common mechanism of antibiotic resistance, one which has been implicated for pleuromutilin.  Modifying the ribosome with enzymes is yet another mechanism seen for many ribosome-targeting antibiotics.  Typically this involves methylation of specific nucleotides in ribosomal RNA by a methylase.  And indeed, one has been observed -- a very worrisome one which confers resistance to a number of different ribosome-targeting antibacterials:

The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics.

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