Thread: beta lactamase inhibitors.

antibiotics like amoxicillin have become useless aganist some super bacteria. so they produce an enzyme beta lactamase which stops the key beta lactum ring in such penicillins from working. by breaking the lactum ring before it has a chance to stop the bacteria. Just a form of micro evolution correct?

so we add inhibitors such as Clavulanic acid.

i was just wondering if anyone could tell me if its just the shape of the Clavulanic acid (also containing the lactum ring) which inhibits the enzyme from breaking down the lactum ring in the antibiotic.

dose it simply give the enzyme an easy way to work. by supplying a similar shape on which the enzyme can work on. The Clavulanic acid has a similar to the point it has a beta lactum ring (4 members highly strained) and a 5 memberd ring. Is that what our lil enzymes work on??

is it possible, that the bacteria could further evolve this enzyme to ignore these inhibitors?

(i was looking at the likes of Augmentin in thinkin, a x/y mix of amoxicillin and Clavulanic acid, and i enjoyed lookin it up anyways, just was wondering if anyone could give me a clearer answer to the one i got)

When I tried to find the exact chemical structure of Clavulanic acid to answer your question I found in wikipedia that it worked as a competitive inhibitors (how I also reckoned it did).

This means it competes with the binding site of the amoxicillin on the enzyme; but while binding it does not react and prevents the reaction with amoxicillin (since it can not bind anymore)

just look up competitive inhibition

A new resistance against the inhibitor is possible, but probably there will not be that many options available to modify the enzyme exactly so it still binds amoxicillin but not clavulanic acid.
Because most mutations which result in low binding affinity toward clavulanic acid will also have their effect on the binding capacities on amoxicillin. But for the exact answer we need how the molecules exactly bind.

excelent.

right, i understand that a bit better now someone has explained it. even if the article said the same

I wonder , how dose the enzyme or rather the inhibitor step up to bind first? electronegitivity values?

what about a new enzyme? would you think that possible?

Indeed the better affinity the inhibitor has over the substrate (antibiotic is this case) the better the inhibition will occur.

In this case I think the steric disturbance of amoxicillin will cause it to have a lower affinity, since it much smaller.
Do not know the dissociation constants

There are many way for a bacteria to become resistant to antibiotics there are two modes of action.
1) bringing less antibiotics to the target (by breaking down or being less permeable to the AB)
2) Making the target less sensitive (other metabolic pathways, lower affinity)

For other enzymes which could do detoxification? I would place my bet on cytochrome P450, I do not know that much on bacteria resistance, but in insects resistance this is a real winner. It acts by making the substance more polair and thus more efficient to get rid of.

Ah thank you , im getting clearer answers than when i read it myself (its always easier and lazy when people lay things out better than wikipedia . I feel guilty now)

Last question - Is it possible to synthesise drugs (and indeed other molecules) so they have a very high affinity to target specialised bits an bobs (e.g. in the body?) i guess not, as the elements need to be fit to bond properly. would it be safe to say that there are limits to the possibility's of attraction due to electronegativity. a kind of range?

thanks for all your help. This was a learning experience on something that really got me thinking.


Damien

In my opinion this is the future of medicine making and not how we often find them today (blindly testing all kinds of different chemicals or just by chance).

By X-Ray crystallography one can know the structures of enzymes and know the structural differences between the active and non-active enzyme and by design molecules act on it.