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The BBC News article Ultra-tough antibiotic to fight superbugs says (in part):

One hard-to-treat infection that has been worrying doctors is vancomycin-resistant enterococci or VRE.

It has been found in hospitals, can cause dangerous wound and bloodstream infections and is considered by the WHO to be one of the drug-resistant bacteria that pose the greatest threat to human health.

Some antibiotics still work against VRE, but the 60-year-old drug vancomycin is now powerless.

The Scripps team set out to see if they could revamp vancomycin to restore its killing ability.

They made some strategic modifications to the molecular structure of the old drug to make it better at attacking bacteria where it hurts - destroying cell walls.

Three changes in particular seem to be important, increasing the strength and durability of the drug.

Lead researcher Dr Dale Boger explained: "We made one change to the molecule vancomycin that overcomes what is the present resistance to vancomycin. And then we added to the molecule, two small changes that built into the molecule, two additional ways in which it can kill bacteria. So the antibiotic has three different, we call them 'mechanisms', by which it kills bacteria. And resistance to such an antibiotic would be very difficult to emerge. So it's a molecule designed specifically to address the emergence of resistance." (emphasis added)

Unfortunately I haven't been able to see the PNAS paper. The link in the BBC article just gives me this:

enter image description here

However the title in PNAS seems to be stated in the Genetic Engineering & Biotechnology News article Vancomycin Modified to Combat Growing Antibiotic Resistance Threat as "Peripheral Modifications of [Ψ[CH2NH]Tpg4]Vancomycin with Added Synergistic Mechanisms of Action Provide Durable and Potent Antibiotics"

It sounds to me that the first change was to keep the original vancomycin's original mode of action but to make it more robust against adaptations in the vancomycin-resistant strain, but I'm not sure if that's correct.

The other two differences sound to me like two new mechanisms that were not there before - it almost sounds like they could just as well be on different molecules administered simultaneously, and that their presence on the vancomycin molecule is primarily for issues of delivery.

Are these two new changes essentially independent modes of actions that could be on separate molecules, or do they need to reside on the same molecule as the primary mechanism?

The article puts the word "mechanism" in quotes. I'm trying to understand if these are independent or work together at the molecular level - in other words do they operate together in such a way that they need to be on the same molecule?

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  • $\begingroup$ Unfortunately we have to wait until this paper is published and then see what the exact mechanism and the modifications are. My guess is that they chemically modified Vancomycin, but this can be wrong. $\endgroup$ – Chris May 30 '17 at 13:50
  • $\begingroup$ @Chris Oh, so it is not just me - nobody can see the paper yet? I thought it was just paywalled. I can't see how "They made some strategic modifications to the molecular structure..." could be interpreted in any other way than "chemically modified". $\endgroup$ – uhoh May 30 '17 at 13:57
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    $\begingroup$ You can't see this paper unless you are a registered journalist. It is still under embargo until it is released - journalists only get access to it to get some more publicity. But I found some interesting information, I "only" have to write up the answer... $\endgroup$ – Chris May 30 '17 at 14:00
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    $\begingroup$ you can find some information about it on the "In the Pipeline" blog from Derek Lowe (blogs.sciencemag.org/pipeline/archives/2017/05/30/…), but the link there also fails for me, so it looks like the embargo date is wrong for some reason. $\endgroup$ – Mad Scientist May 30 '17 at 14:00
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    $\begingroup$ Since PNAS comes out weekly, my guess would be that the article is included in the issue which comes out today or the one next week. I will have a look at it. $\endgroup$ – Chris May 30 '17 at 14:26
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This is typically for a paper under embargo - it can be accessed by registered journalists so they can cover the original article when it is published. The paper is now published, so I changed the first answer.

Before I go into the details, it is necessary to have a short look at the working mechanism of Vancomycin and the way bacteria got around it (which took exceptionally long given that the drug is used since 1959 in the clinic):

Vancomycin works by inhibiting the proper crosslinking of the bacterial peptidoglycan in the cell wall. This is achieved by binding to the substrate for the peptido glycane synthesis, a D-alanyl-D-alanine end of a peptide. Cells then burst due to osmotic pressure.

Resistant cells have a D-alanyl-D-lactate ending of this peptide (all details can be found here or in the introduction of the paper) which lowers the effictivity of the drug by a factor of 1000. Interestingly, this resistance mechanism seems not to have evolved in pathogen bacteria itself, but has been "borrowed" from bacteria which produce Vancomycin and need this as a self-defense (for more, see reference 2).

Vancomycin forms a pocket around the d-Ala-d-Ala substrate, which is impaired in the resistant form. Overcoming the resistance means finding a variation of Vancomycin which effectively binds both of the variants and thus inhibits proper cell wall crosslinking.

To achieve this, Okano and his colleagues chemically modified the structure of Vancomycin with several different functional groups at different sites of the molecule, see this figure from the paper (figure 4 from reference 1):

enter image description here

Changing these residues changes the sensitivity against these modified Vancomycine quite a lot, as can be seen in the sensitivity table in the figure.

enter image description here

When they changed the molecule, they did not only change the binding pocket to allow binding to the different peptide substrates, they also introduced two other independent mechanisms against the bacteria. The most active compound (named 18 in the paper, seen above from figure 11) shows:

Compound 18, which incorporates the redesigned pocket modification for dual d-Ala-d-Ala/d-Ala-d-Lac binding (blocks cell wall synthesis by ligand binding, including inhibition of transpeptidase-catalyzed cross-linking), the CBP disaccharide modification (blocks cell wall synthesis by direct transglycosylase inhibition without d-Ala-d-Ala/d-Ala-d-Lac binding), and the C1 quaternary ammonium salt C-terminal modification (induces membrane permeability), exhibited the most potent inhibition of cell wall synthesis in the assay of all compounds assessed.

Okano and colleagues also tested the different modifications one by one to see, which one has which effect and also tested the effectivity on resistant bacteria. The resulting table shows that the strongest effect is only achieved when all three modifications are present in the molecule.

enter image description here

Since these are independent mechanisms, it will also prolong the time until resistance against the new version of Vancomycin (given that is has a tolerable toxicity in humans and can be introduced into the clinic) will take a while to develop. Despite the optimism in parts of the paper this resistance will eventually develop, although it is quite complicated to overcome three different mechanisms.

References:

  1. Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics
  2. Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms.
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  • $\begingroup$ My goodness! Did you have this already written and ready to go? This was quick, thanks! Certainly helps to have further reading. It will take me a while to read these. In the mean time, it it likely that these changes must all be on the same molecule to work together, as compared to simply dosing with three drugs, each with one of the changes? $\endgroup$ – uhoh May 30 '17 at 14:30
  • $\begingroup$ +1 I don't get to read papers like this anymore, so it was a refreshing answer. Now the cynical me wonders how many more thousands of times more expensive this new and improved vancomycin will cost to use. :-/ $\endgroup$ – anongoodnurse May 30 '17 at 14:31
  • $\begingroup$ @uhoh Nope, I looked this up. Googling the the compound named helped, finding and pinning down information is critical and something I learned over the years in research :-) Plus: This topic interests me, so I read about it every now and then. $\endgroup$ – Chris May 30 '17 at 14:43
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    $\begingroup$ The paper is out now and they use the components mentioned above. I will update the answer tomorrow. @anongoodnurse They mention no lytic activity against RBC, and also see no growth inhibition in cell based assays. Animal experiments as well as toxicity and tolerance studies in humans of course need to be done, but it looks pretty much like there is not much toxicity. $\endgroup$ – Chris May 30 '17 at 18:29
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    $\begingroup$ @uhoh The different mechanisms work independently, and it makes the component more potent. The 1000x more activity comes from the combination of all three. Nevertheless, the other two (not the substrate binding) could be of interest in similar antibiotics. $\endgroup$ – Chris May 31 '17 at 8:58

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