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Beta-lactam antibiotics

The mechanism of action of beta-lactam antibiotics. Created by Jay.

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Video transcript

Lecturer: In this video we're going to look at beta-lactam antibiotics. Lactams are technically amides, however they're different from typical amides. First let's look at a typical amide. We know that the lone pair of electrons on nitrogen is not localized to the nitrogen, it's delocalized, it participates in resonance. When we drew the resonance structure for an amide, this top oxygen here gets a negative one formal charge, and it would be a double bond between the carbon and the nitrogens. Let me go ahead and draw in our groups. That would give the nitrogen a plus one formal charge. If we look at the resonance structure on the right and we think about the hybridization state of nitrogen in this resonance structure, it's obviously Sp2 hybridized here, indicating that the nitrogen is planar. In an ideal amide the planar nitrogen gives the best overlap of orbitals. That allows this lone pair of electrons to be delocalized, which increases the electron density around our carbonyl carbon, so that makes our carbonyl carbon less electrophilic, and therefore less reactive. We said this is why amides are generally unreactive here. That's an ideal amide. There's a special one in penicillin, an amide in a ring, which we call a lactam. Let's look at the general structure for penicillin here, or a penicillin derivative, because you could change the derivative by changing the R group. You could change into amoxicillin or ampicillin or anything like that. Looking for our lactam ring, it's an amide in a ring, and we can see that here is our lactam. If we wanted to classify this lactam, the carbon next to the carbonyl is the alpha carbon. The carbon next to that is the beta carbon, and then we hit the nitrogen. That is why we call this a beta-lactam ring. During World War II there was a huge effort to synthesize penicillin. Chemists didn't know the exact structure, but obviously if you could make it, it would be a huge help in the war effort. It was known that penicillin was easily hydrolyzed in acid or in base, and so some chemists thought that a lactam ring could not be present because there's such strong resonance in amides that it should decrease the reactivity, and it shouldn't be so easy to hydrolyze it. However other chemists like R.B. Woodward favored the beta-lactam structure, and of course those chemists proved to be correct. Woodward thought that this interesting arrangement in penicillin of these two rings, let me go ahead and show you these two rings here. We have a four-membered ring, which is our beta-lactam, and then we have, if you think about this ring as separate over here on the right, a five-member ring. It's a fused four five ring system. If you look at the model structure that I took a picture of over here on the left, you can see that this fused four five ring system prevents the nitrogen from being planar. Let me go ahead and highlight some of these atoms here. This blue atom is the nitrogen. Then we can see that our carbonyls over here on the left, and then there are our fused four five ring system. Thinking about this nitrogen, looking at this geometry here, you can see this bond is up, this bond is up a little bit. This is definitely not a planar nitrogen here, and because it's not planar you're not going to get the same kind of resonance stabilization that we talked about over here. The nitrogen can't donate as much electron density to our carbonyl carbon because of this fused four five ring system, the orbitals don't overlap well enough. Because there isn't as much donation of electron density to our carbonyl carbon, that's going to make this carbonyl carbon more partially positive, more electrophilic and therefore more reactive. That's one of the reasons why this beta-lactam turned out to be easily hydrolyzed. Another reason why this beta-lactam can break is due to ring strain or angle strain. Let's take a look at this fused four five ring system once again. Let me go ahead and use black so we can see what we're talking about here. Here's our beta lactam, I'm going to draw it in here. You can see the nitrogen there in blue. Our four-membered ring. If we think about the hybridization state of, let's say this carbon right here, this carbon is bonded to four atoms, it's Sp3 hybridized. The ideal bond angle for Sp3 hybridized carbon is 109.5 degrees, that's the ideal. We can see that we're far from the ideal in this situation. I'm not sure exactly what it is but it's definitely less than 109.5. If we think about this being a square it might be closer to 90 degrees, somewhere in there. A bond angle of somewhere around 90 degrees, or somewhere close to it, I'm sure it's not exactly 90 degrees, is a deviation from this ideal bond angle of 109.5. The more you deviate from 109.5 the more strain there is, you call that ring strain or angle strain. When you're making a model set you can actually feel these bonds bend, and this gives you an idea about the strain that's present, making this model so that you can actually feel this angle strain. The best way to alleviate that angle strain would be to break the ring, you could hydrolyze your amide. You could break the ring right here and you could see that's what I've drawn over here on the right. We've hydrolyzed our amide, we have relieved this angle strain. Looking at the angle now, this angle has increased, it's no longer somewhere around 90, it's definitely increased, it's gotten closer to our ideal bond angle of 109.5. That's the idea of angle strain or ring strain. Opening the ring alleviates that strain and gets your bond angle closer to the ideal value, if we're thinking about just this carbon, for example, being Sp3 hybridized. We have these two factors that make the beta-lactam ring very reactive. One is there's not as much resonance stabilization and the other one is ring strain. The two of these things combined to make this extremely reactive. Let's take a look at the mechanism of action of penicillin. Here we have our penicillin derivative, and over here we have the trans peptidase enzyme, which is an enzyme in bacteria that's used to build the cell walls of that bacteria. This is the active enzyme right here, and we can see the active enzyme has an OH on it. This OH is going to function as a nucleophile, and it's going to attack our carbonyl carbon right here on our beta-lactam ring. We know that this carbonyl carbon is more electrophilic than for most amides, and we also know that there's significant ring or angle strain here. That's actually the reactive portion of our penicillin derivative molecule. The nucleophile attacks the electrophile, and these electronics will kick off onto your oxygen. Then when you reform the carbonyl, those electrons will move back in to reform the carbonyl, which will kick these electrons off onto the nitrogen. This is pretty much just a nucleophilic acyl substitution method. We're going to break the amide, and let's go ahead and show the product here. What would happen? Well, let me highlight some of these atoms so we can follow along. This oxygen right here is this oxygen. And this carbon right here is this carbon right here. We broke the bond between the carbon and the nitrogen. That would be this nitrogen over here, let me go ahead and circle it. And this nitrogen picked up a proton in the process. The point is we've now disabled the enzyme. This is now a disabled enzyme. There's no longer this free OH here. If it's disabled it can't build cell walls for the bacteria, and if the bacteria can't build cell walls that means that our immune system can fight off any kind of a bacterial infection without a cell wall. This is the idea behind how beta-lactam antibiotics like penicillin work. They prevent the bacteria from building cell walls and then our immune system can do the rest. It all comes down to thinking about the chemistry of this beta-lactam ring.