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GENERAL FEATURES

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These drugs all work by inhibiting the synthesis of the bacterial cell wall.

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You probably guessed this from the title of the chapter. However, this is a really key point. If you can remember this, you are well on your way to learning these drugs.

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The final step in the synthesis of the bacterial cell wall is a cross-linking of adjacent peptidoglycan strands by a process called transpeptidation. The penicillins and cephalosporins are structurally similar to the terminal portion of the peptidoglycan strands and can compete for and bind to the enzymes that catalyze transpeptidation and cross-linking. These enzymes are called penicillin-binding proteins (PBPs). Interference with these enzymes results in the formation of a structurally weakened cell wall, oddly shaped bacteria, and ultimately, death.

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Now, let’s divide the cell wall synthesis inhibitors into two groups based on chemical structure: β-lactams and others.

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β-LACTAMS

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All of the drugs in this group contain a β-lactam ring in their structure.

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Normally, we do not worry too much about the structures of drugs, but in this case we make an important exception. These drugs are often referred to as the β-lactam group. This is because they all have a β-lactam ring in their chemical structure, and it is this β-lactam ring that makes them effective antimicrobials.

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Some bacteria inactivate the β-lactam antibiotics by an enzyme that opens the β-lactam ring.

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Some bacteria contain an enzyme, called β-lactamase, that can open the β-lactam ring (Figure 26–1). This leads to inactivation of the antibiotic. The most common mode of drug resistance is plasmid transfer of the genetic code for the β-lactamase enzyme. There is a β-lactamase specific for the penicillins—it is called penicillinase—and a β-lactamase specific for the cephalosporins—it is called cephalosporinase. Is this easy enough? Inactivation of these drugs by β-lactamases is a major problem and has been the focus of intense research.

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FIGURE 26–1

Here we can see the lactam ring and its opening by penicillinase.

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The inactivation of these drugs by the β-lactamases can be dealt with by two approaches:

  1. Give a β-lactamase inhibitor at the same time.

  2. Make chemical modifications in the structure of the drug to make it more resistant to inactivation.

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CLAVULANIC ACID and SULBACTAM are β-lactamase inhibitors that are given together with the β-lactam drugs to increase their effectiveness.

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One way to increase the effectiveness of the β-lactam antibiotics is to give a β-lactamase inhibitor at the same time. The most commonly used ones are clavulanic acid and sulbactam. You may also come across tazobactam or avibactam.

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The other approach is to chemically modify the structure of the compounds to make the β-lactam ring more ...

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