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Antimicrobial Mechanisms and Resistance

Beta-lactam antibiotic mechanism

All beta-lactam antibiotics (including penicillin) carry a square-shaped beta-lactam ring at the core of their chemical structure. This highly reactive feature is responsible for the antimicrobial effects.

The transpeptidase enzyme (green component in Figure 1 below) is responsible for linking together muramic acid side chains of peptidoglycan (represented by the orange ball chains in figure 1 below). This mesh-linking activity creates a strong cell wall.

Penicillin (purple component in figure 1) can mimic a component of this side chain and as such can irreversibly bind into the enzyme's active site, preventing it from carrying out this crosslinking work. This leads to the degradation of the bacterial cell wall.

Beta-lactam resistance

There are a couple of ways that bacteria can become resistant to beta-lactam antibiotics:

1) Mutation of the transpeptidase active site: This is shown in lower panel C of figure 1. If the antibiotic can no longer bind to the target enzyme due to a conformational change, the drug can't exert its effect anymore. This is shown in the final panel of Figure 1 above.

2) Expression of a lactamase enzyme: Lactamase enzymes cleave the all-important square-shaped beta-lactam ring that is the source of this class of antibiotic's effect. By cutting open the ring before the drug has had a chance to interact with its target, the enzyme can prevent any drug-target binding from taking place.

3) Altered membrane permeability: Changes to the cell wall that prevent or slow down a drug's entry into the cell can confer a degree of resistance. If the drug can't reach the target, it can't have an effect!

4) Active efflux of the drug: Efflux pumps are transmembranal proteins that pump compounds out of the cell. if a bacteria begins to express a pump that can remove a drug quickly, the effect of that drug will be hugely reduced.

The upper images present the mechanism of inhibition of transpeptidase enzyme. Two horizontal rows of yellow spheres represent the bacterial cell wall building blocks. Between them are vertical, parallel orange chains of peptidoglycan, sticking out from the upper and lower yellow spheres. On the upper left image, those orange chains are connected together by the action of a green molecule. On the upper right image the action of the green molecule is inhibited by the purple molecule binding to it. The lower images present resistance of the bacteria on beta-lactam antibiotic. First panel presents normal action of transpeptidase enzyme, middle panel presents the inhibited action of the enzyme by a molecule of beta-lactam antibiotic, and the last panel presents mutated transpeptidase enzyme, which no longer binds antibiotic, so his action is not inhibited.

Figure 1: Penicillin binds the transpeptidase enzyme; this is the mode of function of all beta-lactam antibiotics. In panel A, the enzyme and penicillin are shown separately. In B, we see how the drug fits into the binding site of the enzyme, subsequently preventing normal enzyme function. Bacterial resistance to beta-lactam antibiotics.