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New Vancomycins That Do the Job

I’ve complained in the past (and I’m not the only one) about total synthesis work that doesn’t (or maybe can’t) deliver relevant analogs of the final product. That’s been one of the traditional rationales for the work, but it’s not always followed up on. But here’s one that does: Dale Boger’s group at Scripps has published another paper on modifying vancomycin, work that has grown out of their total synthesis efforts in the area.
This is clearly an area with important applications – in fact, there are three synthetically modified antiobiotics of this kind on the market (oritavancin, dalbavancin, and telavancin. These have modifications, notably the addition of hydrophobic side chains, that both change their activity by helping them bind to the cell membrane, but also (at least for telavancin) also seem to give them new mechanisms of membrane disruption as well.
Vancomycin resistance is known, but it’s been very slow to develop, compared to many other antibiotics. That’s probably because it’s not binding to a protein target (which is directly coded for by the bacterial DNA, providing a way out through mutation). Instead, vancomycin binds to D-Ala-D-Ala, a key component in the construction of the bacterial cell wall. That’s a much harder mechanism for the bacteria to catch on to, as it were, but when they do, it’s very bad news indeed, since vancomycin itself is often a last line of defense in the clinic against infections like MRSA. In this paper, the Boger group is adding one of the commonly used hydrophobic groups (a para-chlorobiphenyl) and simultaneously changing a key amide carbonyl, as found in their earlier binding-pocket work, in the hopes that the double modification would complete evade the defenses of the resistant bacterial strains.
Does it? They report a variety of changes to that amide, and the amidine and methylene variations turn out to have excellent potency against both the wild-type and resistant strains. This is a very nice result indeed, showing that the two modifications can work together, and this could point the way to a new generation of vancomycins that (with any luck) can continue confusing bacteria for many years to come. Congratulations to Boger and his group – this is very difficult chemistry indeed, and it’s being done for excellent reasons. This, in fact, is just the sort of thing that it’s hard to imagine any sort of automated synthesis machine ever being able to perform, and is the kind of high-level work that the advent of such machines should be freeing us up to do. There is no replacement for talented, hard-working organic chemists on projects like this.
Full disclosure: I was a summer undergrad in Boger’s group over thirty years ago – and no, that time frame doesn’t seem very plausible to me, either, but there it is. I did not enjoy myself that much, but neither did the grad student I worked for, I’m pretty sure. I was not exactly an ornament of the lab, and I think that Boger himself was able to deal with my departure at the end of the summer without too much strain.

7 comments on “New Vancomycins That Do the Job”

  1. antibac says:

    excellent work indeed – kudos!

  2. tangent says:

    Yow, I had never looked at the structure of vancomycin. What is it doing with all that structure?

  3. Lars says:

    Slightly off-topic: Earlier versions of the Wikipedia page on vancomycin used to claim that a systematic name could not be assigned to the compound. Now I wonder if such compounds even exist, and what might have been the reasoning behind the original claim. Nowadays, the page does give a systematic name.

  4. Sili says:

    I guess it depends what yo understand by “systematic name”. I gather IUPAC gave up agreeing on a PIN (preferred IUPAC name) for EDTA. There are plenty of systematic names, but it’s hard to say which one is *the* correct.

  5. Sili says:

    I guess it depends what yo understand by “systematic name”. I gather IUPAC gave up agreeing on a PIN (preferred IUPAC name) for EDTA. There are plenty of systematic names, but it’s hard to say which one is *the* correct.

  6. Falanx says:

    A systematic name can be assigned to everything, given enough time with a keyboard and a pencil and paper. It’s whether or not IUPAC sees a reason to. There’s a reason why SMILES came to be after all.

    Also, the continued existence of stupid moety names in systematics like ‘oxirane’ annoys the hell out of me. How difficult is 2,3-epoxypropyl?

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