Chapter 19: Antibiotics and Antimicrobial Drugs
Antibiotics are part of bacterial self-protection
Many antimicrobial compounds are produced by microorganisms as part of their survival
mechanisms. These substances keep other organisms away and protect the host’s supply of
nutrients and oxygen. Molecular mechanisms control the production of these toxic
molecules, preventing self-destruction.
For example, some bacteria restrict the production of antibiotics to the
stationary phase of bacterial growth, when bacteria are not actively
dividing. Others keep the intracellular concentrations at low levels. This is
accomplished by regulating the rates at which these molecules are
produced and exported. In these bacteria, the antibiotic molecules can be
exported in an inactive form that will not affect the producing organism
and become activated by extracellular enzymes.
Some antibiotic producing microorganisms modify their own cell walls or
polymerase molecules to ensure safety. The genes responsible for these
modifications are clustered with the antibiotic producing genes, so that the
functions of these two genes are integrated. When the genes that control
antibiotic production are turned on, the modification to potential
self-targets are made automatically.
Antibiotic spectra
Antibiotics are classified on the basis of targets, effects on microbial growth and range of
microbes they affect. Broad-spectrum antibiotics have an effect on both gram-positive as
well as negative bacteria. Narrow-spectrum antibiotics have an effect on only one group.
1. Antibiotic structure:
Penicillin was the first molecule to be studies structurally in detail for its antimicrobial
properties and has been the template for the development of an entire group of antibiotics.
in its native form, penicillin contains a core four-sided ring structure (β-lactam ring). All
derivatives of penicillin contain this ring structure and are therefore called β-lactam
antibiotics. Derivatives of penicillin such as ampicillin or amoxicillin contain an additional
structure attached to this ring, referred to as a side chain (R). Changing the side chain
changes the antimicrobial activity as well as its resistance to stomach acid and half-life.
1
,Ampicillin, methicillin and amoxicillin all have distinctly different side chains attached to the
nucleus. These examples are referred to as semi-synthetic forms of penicillin, because the
modification can be made in a laboratory. Natural penicillin has a very narrow-spectrum and
reacts against only a small group of gram-positive bacteria.
The same kind of manipulation can be seen with the cephalosporin family, in which
modification of the natural molecule has resulted in five generations of semi-synthetics.
Antibiotic targets
Selective toxicity: the antibiotics should be destructive to the pathogen, but have little or no
effect on the human host. Many chemicals that are useful in restricting bacterial growth are
inherently toxins and cannot be used therapeutically. Penicillin was naturally selectively toxic.
A key point in minimizing toxicity is creating antibiotics with very specific bacterial targets.
Antibiotic targets can be subdivided into: bacterial cell wall, plasma membrane, synthesis of
bacterial proteins, nucleic acids and metabolism.
2
, 1. Bacterial cell wall:
The most appealing target, because it is found in bacteria but not in humans. Antibiotics that
target the bacterial cell wall include penicillins, cephalosporins, carbapenems and
monobactams (all β-lactam antibiotics) and glycopeptides.
Penicillins
Enzymatic interactions take place during the construction of the cell wall components, these
enzymes can be used as targets. The cell wall is composed of layers of peptidoglycan, which
is made up of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acids
(NAM). NAG and NAM molecules are cross-linked through the activity of transpeptidase
enzymes, penicillin-binding proteins (PBP’s). The β-lactam ring of penicillin binds to these
proteins, disrupting bacterial cell wall synthesis by preventing cross-linking of
peptidoglycans. The result is a weak bacterial cell wall unable to withstand the
environmental pressures that are always present.
New cell wall is continuously being built during the active growth phase, so it is at this time
that penicillins are most effective. Gram-negative bacteria have less peptidoglycan in their
cell wall, making them less sensitive to penicillin than gram-positive bacteria. Semi-synthetic
forms of penicillin have enhanced activity against gram-negative bacteria. Mutations in the
bacterial genes that code for PBP’s make organisms resistant to penicillin.
Another mechanism of resistance to penicillins involves the enzyme β-lactamase, which
breaks open the β-lactam ring structure through hydrolysis and nullifies the antibacterial
properties of penicillin. There are augmented forms of penicillin derivatives, for example
augmentin which contains clavulanic acid blocking β-lactamase, which prevent that process.
Cephalosporins
Also contain a β-lactam ring and inhibit the construction of a stable bacterial cell wall.
However, cephalosporins have a greater effect on gram-negative bacteria and are naturally
broad spectrum. They are less susceptible to β-lactamase enzymes than penicillins. There are
five generations of cephalosporins, with the fifth generation being used against resistant
infections such as MRSA.
The mechanism of actions is similar to that of penicillins, but cephalosporins have the
capacity to penetrate through porin molecules found in the outer layer of gram-negative
bacteria. As the side chains of cephalosporins continue to be modified, the spectrum of
reactivity increases.
Carbapenems
Also contain a β-lactam ring and inhibit the construction of a stable bacterial cell wall.
However, carbapenems are less susceptible to β-lactamase enzymes than penicillins and
cephalosporins. They reduce the activity of β-lactamase by binding to it. Carbapenems have
a very broad-spectrum of antibacterial activity and are useful against pseudomonas species.
3
Antibiotics are part of bacterial self-protection
Many antimicrobial compounds are produced by microorganisms as part of their survival
mechanisms. These substances keep other organisms away and protect the host’s supply of
nutrients and oxygen. Molecular mechanisms control the production of these toxic
molecules, preventing self-destruction.
For example, some bacteria restrict the production of antibiotics to the
stationary phase of bacterial growth, when bacteria are not actively
dividing. Others keep the intracellular concentrations at low levels. This is
accomplished by regulating the rates at which these molecules are
produced and exported. In these bacteria, the antibiotic molecules can be
exported in an inactive form that will not affect the producing organism
and become activated by extracellular enzymes.
Some antibiotic producing microorganisms modify their own cell walls or
polymerase molecules to ensure safety. The genes responsible for these
modifications are clustered with the antibiotic producing genes, so that the
functions of these two genes are integrated. When the genes that control
antibiotic production are turned on, the modification to potential
self-targets are made automatically.
Antibiotic spectra
Antibiotics are classified on the basis of targets, effects on microbial growth and range of
microbes they affect. Broad-spectrum antibiotics have an effect on both gram-positive as
well as negative bacteria. Narrow-spectrum antibiotics have an effect on only one group.
1. Antibiotic structure:
Penicillin was the first molecule to be studies structurally in detail for its antimicrobial
properties and has been the template for the development of an entire group of antibiotics.
in its native form, penicillin contains a core four-sided ring structure (β-lactam ring). All
derivatives of penicillin contain this ring structure and are therefore called β-lactam
antibiotics. Derivatives of penicillin such as ampicillin or amoxicillin contain an additional
structure attached to this ring, referred to as a side chain (R). Changing the side chain
changes the antimicrobial activity as well as its resistance to stomach acid and half-life.
1
,Ampicillin, methicillin and amoxicillin all have distinctly different side chains attached to the
nucleus. These examples are referred to as semi-synthetic forms of penicillin, because the
modification can be made in a laboratory. Natural penicillin has a very narrow-spectrum and
reacts against only a small group of gram-positive bacteria.
The same kind of manipulation can be seen with the cephalosporin family, in which
modification of the natural molecule has resulted in five generations of semi-synthetics.
Antibiotic targets
Selective toxicity: the antibiotics should be destructive to the pathogen, but have little or no
effect on the human host. Many chemicals that are useful in restricting bacterial growth are
inherently toxins and cannot be used therapeutically. Penicillin was naturally selectively toxic.
A key point in minimizing toxicity is creating antibiotics with very specific bacterial targets.
Antibiotic targets can be subdivided into: bacterial cell wall, plasma membrane, synthesis of
bacterial proteins, nucleic acids and metabolism.
2
, 1. Bacterial cell wall:
The most appealing target, because it is found in bacteria but not in humans. Antibiotics that
target the bacterial cell wall include penicillins, cephalosporins, carbapenems and
monobactams (all β-lactam antibiotics) and glycopeptides.
Penicillins
Enzymatic interactions take place during the construction of the cell wall components, these
enzymes can be used as targets. The cell wall is composed of layers of peptidoglycan, which
is made up of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acids
(NAM). NAG and NAM molecules are cross-linked through the activity of transpeptidase
enzymes, penicillin-binding proteins (PBP’s). The β-lactam ring of penicillin binds to these
proteins, disrupting bacterial cell wall synthesis by preventing cross-linking of
peptidoglycans. The result is a weak bacterial cell wall unable to withstand the
environmental pressures that are always present.
New cell wall is continuously being built during the active growth phase, so it is at this time
that penicillins are most effective. Gram-negative bacteria have less peptidoglycan in their
cell wall, making them less sensitive to penicillin than gram-positive bacteria. Semi-synthetic
forms of penicillin have enhanced activity against gram-negative bacteria. Mutations in the
bacterial genes that code for PBP’s make organisms resistant to penicillin.
Another mechanism of resistance to penicillins involves the enzyme β-lactamase, which
breaks open the β-lactam ring structure through hydrolysis and nullifies the antibacterial
properties of penicillin. There are augmented forms of penicillin derivatives, for example
augmentin which contains clavulanic acid blocking β-lactamase, which prevent that process.
Cephalosporins
Also contain a β-lactam ring and inhibit the construction of a stable bacterial cell wall.
However, cephalosporins have a greater effect on gram-negative bacteria and are naturally
broad spectrum. They are less susceptible to β-lactamase enzymes than penicillins. There are
five generations of cephalosporins, with the fifth generation being used against resistant
infections such as MRSA.
The mechanism of actions is similar to that of penicillins, but cephalosporins have the
capacity to penetrate through porin molecules found in the outer layer of gram-negative
bacteria. As the side chains of cephalosporins continue to be modified, the spectrum of
reactivity increases.
Carbapenems
Also contain a β-lactam ring and inhibit the construction of a stable bacterial cell wall.
However, carbapenems are less susceptible to β-lactamase enzymes than penicillins and
cephalosporins. They reduce the activity of β-lactamase by binding to it. Carbapenems have
a very broad-spectrum of antibacterial activity and are useful against pseudomonas species.
3
