Antibiotics

Abstract

Antibiotics are natural and synthetic compounds with selective bactericidal or bacteriostatic effects that eliminate pathogens or slow their growth such that the host defence mechanisms can clear the infection. Antibiotics are classified mechanistically according to their site of action in the bacterial cell.

Keywords: antibiotics; antibacterial agents; mechanism of action

Figure 1.

Mechanisms of antibiotic action. Schematic illustrating the mode of action of antibiotics on bacteria according to the target site of each group of agents. The principal processes inhibited by antibiotics are nucleotide biosynthesis, DNA replication, RNA transcription, and protein synthesis. In addition, some peptide antibiotics disrupt bacterial cytoplasmic membrane integrity. A limited number of antibiotics, e.g. ethambutol, ethionamide and isoniazid, specifically inhibit cell wall synthesis in mycobacteria, since the targets for these drugs are not found in other bacteria (see text).

Figure 2.

The tetrahydrofolic acid biosynthetic pathway in bacteria and mammals and its inhibition by sulfamethoxazole (Sx) and trimethoprim (Tp). A reduced form of folic acid, tetrahydrofolic acid, is an important cofactor in the biosynthesis of nucleotides and is required for growth by both bacterial (a) and mammalian (b) cells. Because mammalian cells are unable to synthesize folic acid (b), this compound must be supplied in the diet and is taken into mammalian cells by an active transport mechanism. Since folic acid does not enter most bacterial cells, bacteria synthesize tetrahydrofolic acid intracellularly in a three‐stage process (a) involving the enzymes dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). The presence of DHPS in bacteria (and its absence in mammalian cells) is the basis of the selective action of sulfamethoxazole and other sulfonamides. These drugs are structural analogues of p‐aminobenzoic acid (PABA), and bind more tightly to DHPS than does PABA itself. Although DHFR is present in both bacterial and mammalian cells, trimethoprim is a much more potent inhibitor of the bacterial enzyme, thereby accounting for the antibacterial activity of this drug.

Figure 3.

Bacterial protein synthesis showing the steps inhibited by antibiotics. In the first stage of bacterial protein synthesis, mRNA, transcribed from a structural gene, binds to the smaller (30S) ribosomal subunit and attracts formylmethionine‐tRNA to the initiator codon AUG. The larger (50S) subunit is then added to form a complete (70S) initiation complex. The site occupied by the formylmethionine‐tRNA is called the P (peptidyl donor) site. Adjacent to the P site is the A (aminoacyl acceptor) site, which is aligned with the next trinucleotide codon of the mRNA (the example in the diagram is GCU). Transfer RNA (tRNA) bearing the appropriate anticodon and its specific amino acid (alanine in the example for the diagram) enters the A site, and the ribosomal enzyme peptidyltransferase joins formylmethionine to the second amino acid, resulting in formation of the first peptide bond in the nascent protein. The next step is a translocation event that removes the tRNA with its attached dipeptide to the P site and concomitantly aligns the next triplet codon (the example in the diagram is CGC) with the now vacant A site. The appropriate aminoacyl‐tRNA enters the A site and the transfer process and subsequent translocation steps are completed in a repetitive fashion, known as the elongation cycle, to synthesize the growing polypeptide chain. Finally, a so‐called ‘nonsense’ codon is encountered on the mRNA that signals chain termination and release of the peptide product. The mRNA disengages from the 70S ribosome complex, which dissociates into its two subunits (30S and 50S), ready to form a new initiation complex.

Many antibiotics (indicated) interfere with the process of protein synthesis. Apart from linezolid (a member of the oxazolidinone class), which inhibits the formation of the 70S initiation complex, other antibiotics disrupt events occurring in the elongation cycle. The processes, or activities, inhibited by the various antibiotics are indicated by shaded boxes.

Figure 4.

Bacterial peptidoglycan synthesis and its inhibition by antibiotics. The first dedicated step in bacterial peptidoglycan synthesis involves the synthesis of N‐acetylmuramic acid (NAMA) from N‐acetylglucosamine (NAG) by the addition of a lactic acid substituent, derived from phosphoenolpyruvate, to NAG. This reaction is blocked by fosfomycin, which inhibits the pyruvyltransferase catalysing the conversion of NAG to NAMA. The first three amino acids of the pentapeptide chain of the NAMA–pentapeptide unit are added sequentially, but the terminal D‐alanyl‐D‐alanine is added as a dipeptide unit. To synthesize this unit, the natural form of the amino acid, L‐alanine, is racemized to the D‐form, and two molecules are linked by a ligase. Both of these steps are blocked by the antibiotic cycloserine. When the NAMA‐pentapeptide has been synthesized, a NAG unit is added and the disaccharide complex is passed to a lipid carrier that translocates the whole unit across the cytoplasmic membrane for transfer (transglycosylation) into the growing point of peptidoglycan. The process of transglycosylation is inhibited by the glycopeptide antibiotics. During the translocation process, the lipid carrier acquires an additional phosphate group, which must be removed to regenerate the native carrier for another round of translocation. This recycling process is blocked by bacitracin. The final step in peptidoglycan synthesis involves crosslinking of peptide side‐chains by transpeptidases. The activity of these enzymes is inhibited by the β‐lactam antibiotics.

Figure 5.

Interaction of vancomycin with the peptidoglycan precursor NAG–NAMA–pentapeptide. Vancomycin (a) interacts with nascent peptidoglycan (b) through key hydrogen‐bonding interactions (dashed lines) between functional groups on the antibiotic and sites in the D‐alanyl‐D‐alanine dipeptide unit of NAMA–pentapeptide. Binding of vancomycin to nascent peptidoglycan prevents translocation, whereby NAG–NAMA–pentapeptide units are normally inserted into growing peptidoglycan (see Figure ). Only the L‐lysyl‐D‐alanyl‐D‐alanine component of the NAG–NAMA–pentapeptide is illustrated. This represents the typical vancomycin ligand found in vancomycin‐sensitive Gram‐positive cocci. Reproduced with permission from Strohl WR (ed.) Biotechnology of Antibiotics, 2nd edn. New York: Marcel Dekker.

Figure 6.

Mechanism of the transpeptidase reaction mediating cross‐linkage of bacterial peptidoglycan (upper) and its inhibition by β‐lactam antibiotics (lower). The final stage of peptidoglycan synthesis involves crosslinkage between adjacent peptide side‐chains of the NAG–NAMA–pentapeptide units. This requires the activity of a transpeptidase, containing an active‐site serine, which recognizes the terminal D‐alanyl‐D‐alanine unit (a). The enzyme removes the terminal D‐alanine unit in the nascent peptidoglycan of one side‐chain to give an intermediate acylated D‐alanine–enzyme complex. This is linked to the NAG–NAMA–tetrapeptide through the newly exposed (second) D‐alanine residue. Completion of the transpeptidation reaction results in the formation of a peptide bond between the carboxyl group of D‐alanine in the tetrapeptide unit and the amino group (amino acceptor) of the amino acid at the third position of the NAG–NAMA–pentapeptide of a neighbouring peptidoglycan chain. During this process the transpeptidase is liberated to participate in a further round of crosslinking.

Penicillin (and other β‐lactam antibiotics) are structural analogues of the terminal d‐alanyl‐d‐alanine unit that participates in transpeptidation (b). Consequently β‐lactam antibiotics are able to acylate active‐site serine residues within transpeptidases to form inactive (penicilloyl) enzyme complexes. This results in inhibition of transpeptidation. With potent β‐lactam antibiotics, regeneration of a functional transpeptidase through hydrolysis of the enzyme – β‐lactam complex is inefficient. Reproduced with permission from Dax SL (1997) Antimicrobial Chemotherapeutic Agents. London: Blackie Academic and Professional.

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References

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Further Reading

Chopra I and Brennan P (1998) Molecular action of anti‐mycobacterial agents. Tubercle and Lung Disease 78: 89–98.

Drlica K (1999) Mechanisms of fluoroquinolone action. Current Opinion in Microbiology 2: 504–508.

Franklin TJ and Snow GA (1998) Biochemistry and Molecular Biology of Antimicrobial Drug Action, 5th edn. Dordrecht: Kluwer Academic Publishers.

Gale EF, Cundliffe E, Reynolds PE and Richmond MH (1981) The Molecular Basis of Antibiotic Action, 2nd edn. London: John Wiley and Sons.

Russell AD and Chopra I (1996) Understanding Antibacterial Action and Resistance, 2nd edn. London: Ellis Horwood.

Scholar EM and Pratt WB (2000) The Antimicrobial Drugs, 2nd edn. Oxford: Oxford University Press.

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Chopra, Ian(Aug 2001) Antibiotics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0002225]