Antibacterial drugs are used to treat bacterial infections. Many species of bacteria cause disease in humans; these are termed pathogens . It was once thought that these pathogenic bacteria had a special ability to cause infections whereas bacteria that lived happily and innocuously within the mammalian organism, termed commensals , lacked this ability. It is now known that commensals – and also bacteria in the environment that are normally harmless – are virtually all capable of being pathogenic. In the healthy host, the immune/inflammatory response prevents these inoffensive organisms from giving rise to infections; however, if the immune system is compromised, as in patients infected with human immunodeficiency virus (HIV) or after the use of immunosuppressant drugs, these bacteria can be opportunistic and cause disease.
Antibacterial drugs can be bactericidal , i.e. they kill the bacterium, or they can be bacteriostatic , i.e. they stop the bacterium growing. With these latter drugs, the enfeebled organism is easier for the host’s defence mechanisms to eliminate the bacteria. If these mechanisms are impaired, only bactericidal drugs are effective.
The term antibiotic , originally developed to describe a chemical agent produced by one microorganism that killed or prevented the growth of another microorganism, is now subsumed in the term antibacterial drug . Antibacterial drugs, to be effective, need to manifest selective toxicity, i.e. they should be toxic to the bacterium but innocuous in the human host. However many of the biochemical processes are common to both bacterial and mammalian cells. Nevertheless, there are components and metabolic processes in the bacterial cell that are sufficiently different from those in humans to be targets for antibacterial drugs.
Targets for Antibacterial Drugs
Fig. 30.1 describes the potential targets for selective antibacterial drugs.
The terms Gram-positive and Gram-negative
Many organisms are classified as Gram-positive or Gram-negative. These terms refer to whether the bacteria stain with Gram’s stain, but it has more significance than that of an empirical reaction to a stain. Gram-positive and Gram-negative bacteria differ from each other in several important respects that have implications for the effects of antibiotics.
One important difference is in the structure of the cell wall, which provides support for the plasma membrane and is subject to an internal pressure of approximately 5 atmospheres in Gram-negative organisms and 20 atmospheres in Gram-positive organisms. The bacterial cell wall must, therefore, be able to resist these pressures. Its main constituent is peptidoglycan ( Fig. 30.1 ). Gram-negative bacteria have a single layer of peptidoglycan that in Gram-positive bacteria can be up to 40 layers thick. Each peptidoglycan layer consists of numerous backbones of amino sugars, some having short peptide side-chains that are cross-linked to form a lattice ( Fig. 30.2 ).
There are other differences between the cell wall in Gram-positive and Gram-negative bacteria that are pharmacologically relevant.
The cell wall of Gram-positive organisms is a relatively simple structure, 15–50 nm thick of which 50% is peptidoglycan and about 40% consists of acidic polymer. The latter, being highly polar, favours the penetration of positively charged antibacterial drugs, such as streptomycin, into the cell.
In Gram-negative organisms , the cell wall is thinner but more complex, and it also has an outer membrane (similar in some respects to the plasma membrane) that connects to the single layer of peptidoglycan. The outer membrane contains transmembrane water-filled channels, termed porins , through which hydrophilic antibacterial drugs can move freely. In addition, complex polysaccharides on the outer surface comprise the endotoxins that determine the antigenicity of the organism. In vivo , these can trigger various aspects of the inflammatory reaction.
The lipopolysaccharide of the cell wall is also a major barrier to penetration by benzylpenicillin, methicillin, the macrolides, rifampicin, fusidic acid and vancomycin.
Difficulty in penetrating this complex outer layer is probably the reason why some antibiotics are less active against Gram-negative than Gram-positive bacteria and is the basis of the extraordinary insusceptibility to most antibiotic drugs of Pseudomonas aeruginosa , a pathogen that can cause life-threatening infections in neutropenic patients and in patients with burns and wounds.
Resistance to antibacterial drugs
The genetic determinants of resistance
Mutations of the chromosomal genes in the bacterium are important in methicillin-resistant staphylococci, and in infections with mycoplasma and organisms causing tuberculosis.
Many bacteria have, lying free in the cytoplasm, genetic elements that can replicate on their own. These are closed loops of DNA (termed plasmids ) that can carry resistance genes – often with resistance to several antibiotics. Some stretches of plasmid DNA can be transposed from one plasmid to another and from a plasmid to the chromosome. These stretches are called transposons and they can spread resistance between plasmids ( Fig. 30.3 ).
Transfer of resistance genes between bacteria
This occurs mainly by conjugation, in which protein tubules called sex pili connect two bacteria, allowing transfer of plasmids between them. Genes can also be transferred by phages (bacterial viruses).
The biochemical mechanisms of resistance
There are a number of mechanisms whereby bacteria can become resistant to antibiotics.
Production of enzymes that inactivate the drug
Examples are β-lactamases, which inactivate many penicillins, acetyltransferases, which inactivate chloramphenicol and kinases and other enzymes that inactivate aminoglycosides.
Modification of the drug-binding sites
This occurs with aminoglycosides, erythromycin and penicillin.
Decreased accumulation of the drug in the bacterium
Plasmid-mediated efflux of the drug causes tetracycline resistance in both Gram-positive and Gram-negative organisms and fluoroquinolone resistance in Staphylococcus aureus . Reduced penetration can cause resistance to aminoglycosides, chloramphenicol and glycopeptides.
Alteration of the target enzymes
An example is the plasmid-mediated synthesis of a dihydrofolate reductase that is insensitive to trimethoprim, or of a dihydropteroate synthetase with low affinity for sulphonamides, but unchanged affinity for p -aminobenzoic acid (PABA).
Many pathogenic bacteria have developed resistance to the commonly used antibiotics; important examples include the following:
Some strains of staphylococci (methicillin-resistant Staphylococcus aureus (MRSA)) and enterococci are resistant to virtually all current antibiotics; these organisms can cause virtually untreatable nosocomial (acquired in hospital) infections.
Some strains of Mycobacterium tuberculosis have developed resistance to most antituberculosis drugs.
There are many different classes of antibacterial drugs:
Drugs that affect bacterial peptidoglycan synthesis
Drugs that affect bacterial protein synthesis
Drugs that affect bacterial DNA and RNA synthesis and function
Drugs that affect bacterial folate synthesis and utilization
Drugs that affect peptidoglycan synthesis
These drugs include the penicillins, cephalosporins, monobactams, carbapenems and glycopeptides. The first four are termed β-lactam antibiotics because they all have a β-lactam ring in their structure ( Fig. 30.4 ).
Mechanism of action
The β- lactams inhibit the synthesis of the peptidoglycan corset by inhibiting the enzyme that inserts the cross-links to the peptide chains that are attached to the peptidoglycan backbone ( Figs. 30.5 and 30.6 ). Glycopeptides (e.g. vancomycin) inhibit an earlier reaction. The effect is to weaken the corset enclosing the bacterium. Since the internal osmotic pressure within the organism is high, this leads to rupture of the bacterial cell. These drugs are thus bactericidal .