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02-Finch-ch2-pp 20/5/2002 12:50 pm Page 11 D. Greenwood and R. Whitley
At the basis of all antimicrobial chemotherapy lies the concept of selec- 2.1 Sites of action of antibacterial agents tive toxicity. The necessary selectivity can be achieved in several ways: Principal target
vulnerable targets within the microbe may be absent from the cellsof the host or, alternatively, the analogous targets within the host cells may be sufficiently different, or at least sufficiently inaccessible, for selective attack to be possible. With agents like the polymyxins, the organic arsenicals used in trypanosomiasis, the antifungal polyenes and many antiviral compounds, the gap between toxicity to the microbe and to the host is small, but in most cases antimicrobial agents are able to exploit fundamental differences in structure and function within the microbial cell, and host toxicity generally results The minute size and capacity for very rapid multiplication of bacteria ensures that they are structurally and metabolically very different from mammalian cells and, in theory, there are numerous ways in which bacteria can be selectively killed or disabled. In the event, it turns out that only the bacterial cell wall is structurally unique; other subcellular structures, includ- ing the cytoplasmic membrane, ribosomes and DNA, are built on the same pattern as those of mammalian cells, although suf- ficient differences in construction and organization do exist at these sites to make exploitation of the selective toxicity prin- Antibacterial agents have been discovered – rarely designed – that attack each of these vulnerable sites; the most success-ful compounds seem to be those that interfere with the con- with aminoglycosides and tetracyclines) by active transport struction of the bacterial cell wall, the synthesis of protein, or processes. In the case of Gram-negative organisms the anti- the replication and transcription of DNA. Relatively few clin- biotic must also negotiate an outer membrane, consisting of a ically useful agents act at the level of the cell membrane or by characteristic lipopolysaccharide–lipoprotein complex, which interfering with specific metabolic processes of the bacterial is responsible for preventing many antibiotics from reaching an otherwise sensitive intracellular target. This lipophilic outer Unless the target is located on the outside of the bacterial membrane contains aqueous transmembrane channels cell, antimicrobial agents must be able to penetrate to the site (porins), which selectively allow passage of hydrophilic mole- of action. Access through the cytoplasmic membrane is usually cules depending on their molecular size and ionic charge achieved by passive or facilitated diffusion, or (as, for example, (Figure 2.1). Many antibacterial agents use porins to gain 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 12 C H A P T E R 2 M O D E S O F A C T I O N Fig. 2.1 Diagrammatic representation of the Gram-negative cell envelope. Theperiplasmic space contains the peptidoglycan and some enzymes. (Reproduced withpermission from Russel AD, Quesnel LB, eds, Antibiotics: assessment of antimicrobialactivity and resistance. The Society for Applied Bacteriology Technical Series no. 18,London: Academic Press, p. 62.) access to Gram-negative organisms, although other pathways In addition, the unusual structure of the mycobacterial cell wall is exploited by a number of antituberculosis agents.
Fosfomycin
The N-acetylmuramic acid component of the bacterial cell wallis derived from N-acetylglucosamine by the addition of a lactic Peptidoglycan forms the rigid, shape-maintaining layer of all acid substituent derived from phosphoenolpyruvate.
medically important bacteria except mycoplasmas. Its struc- Fosfomycin blocks this reaction by inhibiting the pyruvyl trans- ture is basically similar in Gram-positive and Gram-negative ferase enzyme involved. The antibiotic enters bacterial cells by organisms, although there are important differences. In both active transport mechanisms for a-glycerophosphate and types of organism the basic macromolecular chain consists of glucose-6-phosphate. Glucose-6-phosphate induces the hexose N-acetylglucosamine alternating with its lactyl ether, N-acetyl- phosphate transport pathway in some organisms (notably muramic acid. Each muramic acid unit carries a pentapeptide, Escherichia coli) and potentiates the activity of fosfomycin the third amino acid of which is L-lysine in most Gram-positive cocci and meso-diaminopimelic acid in Gram-negative bacilli.
The related phosphonic acid, fosmidomycin, uses the same The cell wall is given its rigidity by cross-links between this transport pathways and is also potentiated by glucose-6-phos- amino acid and the penultimate amino acid (which is always phate. However, fosmidomycin acts differently by interfering D-alanine) of adjacent chains, with loss of the terminal amino with the formation of isopentyl diphosphate during isoprenoid acid (also D-alanine) (Figure 2.2). Gram-negative bacilli have biosynthesis.2 The vulnerable enzyme is part of an alternative a very thin peptidoglycan layer, which is loosely cross-linked; mevalonate-independent pathway of isoprenoid biosynthesis Gram-positive cocci, in contrast, possess a very thick peptido- present in E. coli, malaria parasites and the chloroplasts of glycan coat, which is tightly cross-linked through interpeptide higher plants, but Staphylococcus aureus uses the normal meval- bridges. The walls of Gram-positive bacteria also differ in con- onate pathway, which probably explains the intrinsic resistance taining considerable amounts of polymeric sugar alcohol phos- to fosmidomycin of Gram-positive bacteria.3 phates (teichoic and teichuronic acids), while Gram-negativebacteria possess an external membrane-like envelope as Cycloserine
Penicillins, cephalosporins and other b-lactam agents, as The first three amino acids of the pentapeptide chain of well as fosfomycin, cycloserine, bacitracin and the glycopep- muramic acid are added sequentially, but the terminal D- tides vancomycin and teicoplanin, selectively inhibit different alanyl-D-alanine is added as a unit (Figure 2.3). To form this stages in the construction of the peptidoglycan (Figure 2.3).
unit the natural form of the amino acid, L-alanine, must first 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 13 Fig. 2.2 Schematic representations of the terminal stages of cell wall synthesis in Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. See text for explanation. Arrows indicate formation of cross-links, with loss of terminal D-alanine; inGram-negative bacilli many D-alanine residues are not involved in cross-linking and are removed by D-alanine carboxypeptidase. NAG,N-acetylglucosamine; NAMA, N-acetylmuramic acid; ala, alanine; glu, glutamic acid; lys, lysine; gly, glycine; m-DAP, meso-diaminopimelic acid.
Fig. 2.3 Simplified scheme of bacterial cell wall synthesis, showing the sites of action of cell wall active antibiotics. NAG, N-acetylglucosamine; NAMA, N-acetylmuramic acid. (Reproduced from Greenwood D, Antimicrobial Agents in: Greenwood D, Slack RCB,Peutherer JF, eds, 2002 Medical Microbiology 16th edn. Edinburgh: Churchill Livingstone.) be racemized to D-alanine and two molecules are then joined any amino acids needed for the interpeptide bridge of Gram- together by D-alanine synthetase. Both of these reactions are positive organisms. It is then passed to a lipid carrier molecule, blocked by the antibiotic cycloserine, which is a structural which transfers the whole unit across the cell membrane to be added to the growing end of the peptidoglycan macromolecule(Figure 2.3). Addition of the new building block is preventedby the glycopeptides vancomycin and teicoplanin, which bind Glycopeptides
to the acyl-D-alanyl-D-alanine tail of the muramylpentapep- Once the muramylpentapeptide is formed in the cell cyto- tide. Strains of enterococci that are able to replace the termi- plasm, an N-acetylglucosamine unit is added, together with nal D-alanine with D-lactate exhibit resistance to 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 14 C H A P T E R 2 M O D E S O F A C T I O N glycopeptides.4 Because these glycopeptides are large polar in Gram-negative bacilli bind to PBP3; similarly, mecillinam molecules they cannot penetrate the outer membrane of Gram- binds exclusively to PBP2. Most b-lactam antibiotics, when negative organisms, which explains their restricted spectrum present in sufficient concentration, bind to both these sites and to others (PBP1a and PBP1b) that participate in the rapidlylytic response of Gram-negative bacilli to many penicillins andcephalosporins.
Bacitracin
The low-molecular-weight PBPs (4, 5 and 6) of E. coli are The lipid carrier involved in transporting the cell wall build- carboxypeptidases, which may operate to control the extent of ing block across the membrane has been characterized as a C cross-linking in the cell wall. Mutants lacking these enzymes isoprenyl phosphate. The lipid acquires an additional phos- grow normally and have thus been ruled out as targets for the phate group in the transport process and must be dephospho- inhibitory or lethal actions of b-lactam antibiotics. The PBPs rylated in order to regenerate the native compound for another with higher molecular weights (PBPs 1a, 1b, 2 and 3) possess round of transfer. The cyclic peptide antibiotic bacitracin binds transpeptidase activity, and it seems that these PBPs represent to the isoprenyl pyrophosphate and prevents this dephospho- different forms of the transpeptidase enzyme necessary to rylation. Unfortunately, analogous reactions in eukaryotic cells arrange the complicated architecture of the cylindrical or are also inhibited by bacitracin, and this may be the basis of spherical bacterial cell during growth, septation and division.
The nature of the lethal event
In Gram-negative bacilli, the bactericidal effect of -Lactam antibiotics
antibiotics can be quantitatively prevented by providing suffi- The final cross-linking reaction that gives the bacterial cell wall cient osmotic protection. In these circumstances the bacteria its characteristic rigidity was pinpointed many years ago as the survive as spheroplasts, which readily revert to the bacillary primary target of penicillin and other b-lactam agents. These shape on removal of the antibiotic. It thus seems clear that cell compounds were postulated to inhibit formation of the death in Gram-negative bacilli is a direct consequence of transpeptide bond by virtue of their structural resemblance to osmotic lysis of cells deprived of the protective peptidoglycan the terminal D-alanyl-D-alanine unit that participates in the transpeptidation reaction. This knowledge had to be recon- The nature of the lethal event in Gram-positive cocci is ciled with various concentration-dependent morphological more complex. Since these bacteria possess a much thicker, responses that Gram-negative bacilli undergo on exposure to tougher peptidoglycan layer than that present in the Gram- penicillin and other b-lactam compounds: filamentation negative cell wall, much greater damage has to be inflicted (caused by inhibition of division rather than growth of the bac- before death of the cell ensues. However, one of the first events teria) at low concentrations, and the formation of osmotically that occurs on exposure of Gram-positive cocci to b-lactam fragile spheroplasts (peptidoglycan-deficient forms that have antibiotics is a release of lipoteichoic acid, an event which lost their bacillary shape) at high concentrations.
appears to trigger autolysis of the peptidoglycan.
Three observations suggested that these morphological Optimal dosage effect
For many strains of Gram-positive cocci, an optimal bacteri- The oral cephalosporin cefalexin (and some other b-lactam cidal concentration of b-lactam antibiotics can be identified agents, including cefradine, temocillin and the monobac- above which the killing effect is reduced, sometimes very strik- tam, aztreonam) causes the filamentation response alone ingly. The basis of this effect, often called the ‘Eagle phenom- over an extremely wide range of concentrations.
enon’ after its discoverer, has never been satisfactorily Mecillinam (amdinocillin) does not inhibit division (and explained. A plausible hypothesis is that the lethal event is trig- hence does not cause filamentation in Gram-negative gered by low concentrations of the antibiotic as a consequence bacilli), but has a generalized effect on the bacterial cell of binding to one particular target protein; binding at higher concentrations to other targets (PBPs) stops the bacterial cell Combining cefalexin and mecillinam evokes the ‘typical’ from growing and this antagonizes the lethal effect, which spheroplast response in E. coli that neither agent induces It was subsequently shown that isolated membranes of bac- Persisters
teria contain a number of proteins that are able to bind peni- About 1 in 105 bacteria in a culture exposed to b-lactam antibi- cillin and other b-lactam antibiotics. These penicillin-binding otics survive, even on prolonged exposure to an optimal bac- proteins (PBPs) are numbered in descending order of their tericidal concentration. These ‘persisters’ have not acquired molecular weight according to their separation by polyacry- resistance, since, if the antibiotic is removed and they are lamide gel electrophoresis. The number found in bacterial cells allowed to grow, most of their immediate progeny are killed varies from species to species: E. coli has at least seven and on re-exposure, just as the parent culture is. These bacteria Staph. aureus four. b-Lactam agents that induce filamentation may be cells in which the peptidoglycan exists transiently as a 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 15 complete covalently linked macromolecule. Inhibition by the DNA, binds to the smaller ribosomal subunit and attracts N- antibiotic of autolytic enzymes needed to create growth points formylmethionyl transfer RNA (fMet-tRNA) to the initiator in the peptidoglycan would effectively trap the cells in a state codon AUG. The larger subunit is then added to form a com- in which they could not grow (and therefore could not be plete initiation complex. fMet-tRNA occupies the P (peptidyl killed) until the antibiotic is removed.
donor) site; adjacent to it is the A (aminoacyl acceptor) sitealigned with the next trinucleotide codon of the mRNA.
Tolerance
Transfer RNA (tRNA) bearing the appropriate anticodon, and In some Gram-positive cocci there may be a marked dissoci- its specific amino acid, enters the A site, and a peptidyl trans- ation between the concentrations of b-lactam agents (and gly- ferase joins N-formylmethionine to the new amino acid with copeptides) required to achieve a bacteristatic and a loss (via an exit site) of the tRNA in the P site; the first peptide bactericidal effect. The organisms are not ‘resistant’ since they bond of the protein has been formed. A translocation event remain fully susceptible to the inhibitory activity of the antibi- then moves the remaining tRNA with its dipeptide to the P site otic, although the bactericidal effect is reduced. Defective and concomitantly aligns the next triplet codon of mRNA with autolysins remain the most likely explanation of the effect, the now vacant A site. The appropriate aminoacyl-tRNA enters which has some similarities to the persister phenomenon.6 the A site and the transfer process and subsequent transloca-tion are repeated. In this way, the peptide chain is built up inprecise fashion, faithful to the original DNA blueprint, until a Antimycobacterial agents
so-called ‘nonsense’ codon is encountered on the mRNA that Agents acting specifically against Mycobacterium tuberculosis and signals chain termination and release of the peptide chain. The other mycobacteria have been less well characterized than other mRNA is disengaged from the ribosome, which dissociates into antimicrobial drugs. However, it is thought that several of them its two subunits ready to form a new initiation complex. Within owe their activity to selective effects on the unique structure bacterial cells, many ribosomes are engaged in protein syn- of the mycobacterial envelope.7 Thus, although isoniazid has thesis during active growth, and a single strand of mRNA may been found to interfere with various cellular functions of bac- interact with many ribosomes along its length to form a teria, it is likely that it owes its specific bactericidal activity against M. tuberculosis to interference with mycolic acid syn- Many antibiotics interfere with the process of protein syn- thesis. The effect is achieved by inhibition of a fatty acid desat- thesis (Figure 2.4). Some, like puromycin, which is an analog urase after intracellular oxidation of isoniazid to an active of the aminoacyl tail of charged tRNA and causes premature product.8 Ethionamide, prothionamide and pyrazinamide, chain termination, act on bacterial and mammalian ribosomes which are related nicotinic acid derivatives, are also thought alike and are therefore unsuitable for systemic use in humans.
to undergo intracellular modification and to act in a similar Therapeutically useful inhibitors of protein synthesis include many of the naturally occurring antibiotics, such as chloram- Ethambutol, a slow acting and primarily bacteriostatic phenicol, tetracyclines, aminoglycosides, fusidic acid, antimycobacterial agent, inhibits arabinosyl transferases. These macrolides, lincosamides and streptogramins. Some newer enzymes bring about the polymerization of arabinose to form agents, including mupirocin and the oxazolidinones, also act arabinan, a polysaccharide component of the core polymers of Chloramphenicol
The molecular target for chloramphenicol is the peptidyl trans- ferase enzyme that links amino acids in the growing peptidechain. The effect of the antibiotic is thus to freeze the process The amazing process by which the genetic message in DNA is of chain elongation, bringing bacterial growth to an abrupt halt.
translated into large and unique protein molecules is univer- The process is completely reversible, and chloramphenicol is sal; in prokaryotic, as in eukaryotic cells, the workbench is the fundamentally a bacteristatic agent. The binding of chloram- ribosome, composed of two distinct subunits, each a complex phenicol to the 50S subunit of 70S ribosomes is highly specif- of ribosomal RNA (rRNA) and numerous proteins. However, ic. The basis for the rare, but fatal, marrow aplasia associated bacterial ribosomes are open to selective attack because they with this compound is not therefore a generalized effect on differ from their mammalian counterparts in both protein and mammalian protein synthesis, although mitochondrial ribo- RNA content; indeed they can be readily distinguished in the somes, which are similar to those of bacteria, may be involved.
ultracentrifuge: bacterial ribosomes exhibit a sedimentationcoefficient of 70S (composed of 30S and 50S subunits), Tetracyclines
whereas mammalian ribosomes display a coefficient of 80S(composed of 40S and 60S subunits).
Antibiotics of the tetracycline group are actively transported In the first stage of bacterial protein synthesis, messenger into bacterial cells and attach to 30S ribosomal subunits in RNA (mRNA), transcribed from the appropriate region of such a manner as to prevent binding of incoming aminoacyl- 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 16 C H A P T E R 2 M O D E S O F A C T I O N Linezolid
INITIATION
Streptomycin
Gentamicin
Tetracyclines
ELONGATION
Tobramycin
accurate reading of genetic code and association of peptidyl- tRNA Amikacin
Fusidic acid
Macrolides
TERMINATION
Chloramphenicol
Spectinomycin
Lincosamides
Streptogramins

Fig. 2.4 The process of protein synthesis and the steps inhibited by various antibacterial agents. (Adapted from Chopra I, GreenwoodD, Antibacterial agents: basis of action, in: Encyclopedia of Life Sciences, Nature Publishing Group, London: www.els.net). PERMISSIONNOT YET RECEIVED.
tRNA to the A site.9 The effect is to halt chain elongation and, one site on the ribosome, whereas streptomycin binds in a 1:1 like chloramphenicol, these antibiotics are predominantly bac- ratio at a unique site. One consequence of this is that single- step, high-level resistance to streptomycin, which is due to a Tetracyclines also penetrate into mammalian cells (indeed, change in a specific protein of the 30S ribosomal subunit, does the effect on chlamydiae depends on this) and can interfere not extend to other aminoglycosides.
with protein synthesis on eukaryotic ribosomes. Fortunately, Elucidation of the mode of action of aminoglycosides has cytoplasmic ribosomes are not affected at the concentrations been complicated by the need to reconcile a variety of enig- achieved during therapy, although mitochondrial ribosomes are. The selective toxicity of tetracyclines thus presents some-thing of a puzzle, the solution to which is presumably that these ● Streptomycin and other aminoglycosides cause misreading antibiotics are not actively concentrated by mitochondria as of mRNA on the ribosome while paradoxically halting pro- they are by bacteria and concentrations reached are insufficient tein synthesis completely by interfering with the formation ● Inhibition of protein synthesis by aminoglycosides leads not just to bacteriostasis as with, for example, tetracycline Aminoglycosides
or chloramphenicol, but also to rapid cell death.
Much of the literature on the mode of action of aminoglyco- ● Susceptible bacteria (but not those with resistant ribo- sides has concentrated on streptomycin. However, the action somes) quickly become leaky to small molecules on expo- of gentamicin and other deoxystreptamine-containing amino- sure to the drug, apparently because of an effect on the cell glycosides is clearly not identical, since they bind at more than 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 17 ● Mutations can occur that render the bacterial cell depen- to other macrolides, lincosamides and streptogramin B in the ● Susceptibility is dominant over resistance in merozygotes The detailed mode of action of these antibiotics has not yet that are diploid for the two allelic forms.
been definitively worked out. Erythromycin (like type A strep-togramins; see below) binds almost exclusively to free ribo- A well-lit path through this maze has not yet been defini- somes and brings protein synthesis to a halt after formation of tively charted, but the situation is slowly becoming clearer. The the initiation complex, probably by interfering with the translo- two effects of aminoglycosides on initiation and misreading cation reaction. The precise mechanism of action of lin- may be explained by a concentration-dependent effect on ribo- cosamides is less clear, but they appear to interfere indirectly somes engaged in the formation of the initiation complex and with the peptidyl transferase reaction, possibly by blocking the those in the process of chain elongation:10 in the presence of a sufficiently high concentration of drug, protein synthesis is The streptogramins are composed of two interacting com- completely halted once the mRNA is run off because re-initi- ponents designated A and B (p. 000). The type A molecules ation is blocked; under these circumstances there is little or no bind to 50S ribosomal subunits and affect both donor and opportunity for misreading to occur. However, at concentra- acceptor functions of peptidyl transferase by blocking attach- tions at which only a proportion of the ribosomes can be ment of aminoacyl-tRNA to the catalytic site of the enzyme blocked at initiation, some protein synthesis will take place and and subsequent transfer of the growing peptide chain. Type B the opportunity for misreading will be provided.
streptogramins occupy an adjacent site on the ribosome and The dominance of susceptibility over resistance has been prevent formation of the peptide bond, leading to the prema- tentatively explained by the fact that the non-functional initi- ture release of incomplete polypeptides.13 Type A molecules ation complexes formed in the presence of aminoglycosides bind to free ribosomes, but not to polysomes engaged in are unstable, so that the ribosomes continuously dissociate protein synthesis, whereas type B can prevent further synthe- from mRNA and recycle in an inoperative form. These crip- sis during active synthesis. The bactericidal synergy between pled ribosomes (of which there are twice as many as there are the two components arises mainly from conformational resistant ones in merozygotes) are hence continuously made changes induced by Type A molecules that improve the re-available to sequester newly formed mRNA and prevent the resistant ribosomes from maintaining a supply of the polypep-tides that the cell needs.10 Fusidic acid
The effects of aminoglycosides on membrane permeability, and the potent bactericidal activity of these compounds, Fusidic acid forms a stable complex with an elongation factor remain enigmatic. However, the two phenomena may be (EF-G) involved in translocation and with guanosine triphos- related.11 In bacteria, as in mammalian cells, some of the ribo- phate (GTP), which provides energy for the translocation somes (presumably those engaged in transmembrane protein process. One round of translocation occurs, with hydrolysis of transfer) may be membrane bound. Moreover, aminoglyco- GTP, but the fusidic acid–EF–G–GDP–ribosome complex sides enter bacteria by an active transport process (absent in blocks further chain elongation, leaving peptidyl-tRNA in the anaerobes and streptococci, hence their inherent resistance) that is dependent on protein synthesis. It is possible that site- Although protein synthesis in Gram-negative bacilli – and, specific uptake of the drug at ribosomal attachment sites and indeed, mammalian cells – is susceptible to fusidic acid, the subsequent binding to the ribosome–membrane complex may antibiotic penetrates poorly into these cells and the spectrum lead to membrane leakiness and cell death.12 of action is virtually restricted to Gram-positive bacteria,notably staphylococci.
Spectinomycin
The aminocyclitol antibiotic spectinomycin, often considered
Oxazolidinones
alongside the aminoglycosides, binds in reversible fashion(hence the bacteriostatic activity) to ribosomal RNA of the 30S Linezolid and other oxazolidinones are bacteriostatic agents subunit. There it interrupts the translocation event that occurs that act at an earlier stage than other inhibitors of protein syn- as the next codon of mRNA is aligned with the A site in readi- thesis. They prevent the process by which the 50S ribosomal ness for the incoming aminoacyl-tRNA.
subunit and the 30S unit (charged with mRNA and fMet-tRNA) come together to form the 70S initiation complex.15,16This is achieved by binding to the 50S subunit, at a site close Macrolides, lincosamides, streptogramins
to that of chloramphenicol and lincosamides.17 These antibiotic groups are structurally very different, but bindto closely related sites on the 50S ribosome of bacteria. One Mupirocin
consequence of this is that staphylococci exhibiting inducibleresistance to erythromycin, which is caused by methylation of Mupirocin also has a unique mode of action. The epoxide- certain adenine residues in the rRNA, also become resistant containing monic acid tail of the molecule (see p. 000) is an 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 18 C H A P T E R 2 M O D E S O F A C T I O N analog of isoleucine and, as such, is a competitive inhibitor of made up of four polypeptide subunits, and rifampicin specifi- isoleucyl-tRNA synthetase in bacterial cells.18 It may be a cally binds to the b subunit. However, since isolated b subunit bifunctional inhibitor of the synthetase, since it also binds to does not bind rifampicin, the precise configuration in which it the ATP-binding site of the enzyme.19 The corresponding is locked into the core enzyme is important.
Sulfonamides and diaminopyrimidines
These agents act at separate stages in the pathway of folic acid synthesis and thus act indirectly on DNA synthesis, since theactive form of the co-enzyme, tetrahydrofolic acid, serves as Compounds that bind directly to the double helix are gener- intermediate in the transfer of methyl, formyl and other single- ally highly toxic to mammalian cells and only a few – those that carbon fragments in the biosynthesis of purine nucleotides and interfere with DNA-associated enzymic processes – exhibit suf- thymidylic acid, as well as of some amino acids.
ficient selectivity for systemic use as antibacterial agents. These Sulfonamides are analogues of p-aminobenzoic acid. They compounds include antibacterial quinolones, novobiocin and competitively inhibit dihydropteroate synthetase, the enzyme rifampicin (rifampin). Diaminopyrimidines, sulfonamides, 5- which condenses p-aminobenzoic acid with dihydropteroic acid nitroimidazoles and (probably) nitrofurans also affect DNA in the early stages of folic acid synthesis. Most bacteria need synthesis and will be considered under this heading.
to synthesize folic acid and cannot use exogenous sources ofthe vitamin. Mammalian cells, in contrast, require preformedfolate and this is the basis of the selective action of sulfon- Quinolones
amides. The antileprotic sulfone dapsone, and the antituber- The problem of packaging the enormous circular chromosome culosis drug p-aminosalicylic acid, act in a similar way; the of bacteria (>1 mm long) into a microscopic cell, while making basis for their restricted spectrum may reside in differences of adequate arrangements for transcription and replication, has affinity for variant forms of dihydropteroate synthetase in the necessitated some considerable ingenuity on the part of the microbe. The solution has been to condense the DNA down Diaminopyrimidines act later in the pathway of folate syn- and to twist it into a ‘supercoiled’ state – a process aided by thesis. These compounds inhibit dihydrofolate reductase, the the natural strain imposed on a covalently closed double helix.
enzyme that generates the active form of the co-enzyme The twists are introduced in the opposite sense to those of the tetrahydrofolic acid. In most of the reactions in which tetrahy- double helix itself and the molecule is said to be negatively drofolate takes part it remains unchanged, but in the biosyn- supercoiled. Relaxation and re-establishment of the supercoiled thesis of thymidylic acid tetrahydrofolate acts as hydrogen state involves precisely regulated nicking and resealing of the donor as well as a methyl group carrier and is thus oxidized to DNA strands, accomplished by enzymes called topoisomeras- dihydrofolic acid in the process. Dihydrofolate reductase is es. One topoisomerase, DNA gyrase, is a tetramer composed therefore crucial in recycling tetrahydrofolate, and diaminopy- of two pairs of a and b subunits, and the primary target of the rimidines act relatively quickly to halt bacterial growth.
action of nalidixic acid and other quinolones is the a subunit Sulfonamides, in contrast, cut off the supply of folic acid at of DNA gyrase, although another enzyme, topoisomerase IV, source and act slowly, since the existing folate pool can satisfy is also affected.20 Indeed, in Gram-positive bacteria, topoiso- the needs of the cell for several generations.
merase IV seems to be the main target.21 This enzyme does The selective toxicity of diaminopyrimidines comes about not have supercoiling activity; it appears to be involved in because of differential affinity of these compounds for dihy- relaxation of the DNA chain and chromosomal segregation.
drofolate reductase from various sources. Thus trimethoprim Fortunately, the corresponding mammalian topoisomerases has a vastly greater affinity for the bacterial enzyme than for its are less susceptible to quinolone attack.
mammalian counterpart, pyrimethamine exhibits a particular- Curiously, the coumarin antibiotic novobiocin, which acts ly high affinity for the plasmodial version of the enzyme and, in a complementary fashion by binding specifically to the b- in keeping with its anticancer activity, methotrexate has high subunit of DNA gyrase, displays an exactly opposite spectrum affinity for the enzyme found in mammalian cells.
of activity to that of nalidixic acid.
5-Nitroimidazoles
Rifampicin
The most intensively investigated compound in this group is Rifampicin and other compounds of the ansamycin group metronidazole, but other 5-nitroimidazoles are thought to act specifically inhibit DNA-dependent RNA polymerase; that is, in a similar manner. Metronidazole siphons off electrons from they prevent the transcription of RNA species from the DNA ferredoxin (or other electron transfer proteins with low redox template. Rifampicin is an extremely efficient inhibitor of the potential) causing the nitro group of the drug to be reduced.
bacterial enzyme, but fortunately eukaryotic RNA polymerase It is this reduced and highly reactive intermediate that is is not affected. RNA polymerase consists of a core enzyme responsible for the antimicrobial effect, probably by binding 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 19 to DNA, which undergoes strand breakage.22 The requirement for interaction with low redox systems restricts the activitylargely to anaerobic bacteria and certain protozoa that exhibit In view of the scarcity of antibacterial agents acting on the cyto- anaerobic metabolism. The basis for activity against micro- plasmic membrane, it is surprising to find that the most suc- aerophilic species such as Helicobacter pylori and Gardnerella cessful groups of antifungal agents – the polyenes, azoles, and vaginalis remains speculative, though a novel nitroreductase, allylamines – all achieve their effects in this way.28,29 However, which is altered in metronidazole-resistant strains, is implicat- the echinocandins, the latest addition to the antifungal arma- mentarium, differ in affecting the fungal cell wall.
Nitrofurans
As with nitroimidazoles, the reduction of the nitro group ofnitrofurantoin and other nitrofurans is a prerequisite for The polyenes bind only to membranes containing sterols; ergos- antibacterial activity. Micro-organisms with appropriate terol, the predominant sterol of fungal membranes, appears to nitroreductases act on nitrofurans to produce a highly reactive be particularly susceptible. The effect is to make the membrane electrophilic intermediate and this is postulated to affect DNA leaky, probably by the formation of transmembrane pores. Since as the reduced intermediates of nitroimidazoles do. Other evi- bacterial cell membranes (except those of mycoplasmas) do not dence suggests that the reduced nitrofurans bind to bacterial contain sterols, they are unaffected by polyenes, even in high ribosomes and prevent protein synthesis;24 inducible enzyme concentration; unfortunately, this immunity does not extend to synthesis seems to be particularly susceptible. An effect on sterol-containing mammalian cells, and polyenes consequent- DNA has the virtue of explaining the known mutagenicity of these compounds in vitro and any revised mechanism relatingto inhibition of protein synthesis needs to be reconciled withthis property.
The activity of the antifungal azoles is also dependent on the presence of ergosterol in the fungal cell membrane. These compounds block ergosterol synthesis by interfering with thedemethylation of its precursor, lanosterol.30 Lanosterol Agents acting on cell membranes do not normally discriminate between microbial and mammalian membranes, although the antifungals have much less influence on analogous mammalian fungal cell membrane has proved more amenable to selective systems, some of the side effects are attributable to such action.
attack (see below). The only membrane-active antibacterial Antifungal azole derivatives are predominantly fungistatic agents to be administered systemically in human medicine, but some compounds, notably miconazole and clotrimazole, polymyxin B (now rarely used systemically) and the closely kill fungi at concentrations higher than those which merely related compound colistin (polymyxin E), act like cationic inhibit growth, apparently by causing direct membrane detergents; they disrupt the cytoplasmic membrane of the cell, damage. Other, less well characterized, effects of azoles on probably by attacking the exposed phosphate groups of the fungal respiration have also been described.31 membrane phospholipid. They also have an effect on the exter-nal membrane of Gram-negative bacilli, which might explaintheir preferential action on these organisms. The end result is leakage of cytoplasmic contents and death of the cell. Variousfactors, including growth phase and incubation temperature, The antifungal allylamine derivatives terbinafine and naftifine alter the balance of fatty acids within the bacterial cell mem- inhibit squalene epoxidase, another enzyme involved in the brane, and this can concomitantly affect the response to biosynthesis of ergosterol.32 The fungicidal effect may be due to accumulation of squalene rather than a deficiency of ergos- Several antibiotics, known collectively as ionophores, inter- terol. In Candida albicans the effect is fungistatic and the yeast fere with cation transport in cell membranes. These include form is less susceptible than is mycelial growth. In this species the topical antibiotic gramicidin A, and some agents used in there is less accumulation of squalene than in dermatophytes, veterinary medicine, such as the macrotetralide monensin and and ergosterol deficiency may be the limiting factor.33 the depsipeptide valinomycin. Naturally occurring antimicro-bial peptides, such as the cecropins, magainins and defensins,as well as the lanthionine-containing lantibiotics, disrupt cell membranes, sometimes in a selective manner; some of thesepeptides appear to form aggregates with ionophoric proper- Caspofungin and related compounds inhibit the formation of glucan, an essential polysaccharide of the cell wall of many 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 20 C H A P T E R 2 M O D E S O F A C T I O N fungi, including Pneumocystis carinii. The vulnerable enzyme proved elusive, but it now seems likely that chloroquine and is b-1,3-glucan synthase, which is located in the cell mem- related compounds act primarily by inhibiting haem poly- merase, thus preventing detoxification of ferriprotoporphyrinIX (heme), which is produced from the red cell hemoglobinin the food vacuole of the parasites.36 Ferriprotoporphyrin IX is a toxic metabolite which is normally rendered innocuous bypolymerization; malarial pigment consists of granules of this The spectrum of activity of flucytosine (5-fluorocytosine) is virtually restricted to yeasts. In these fungi flucytosine is trans- Chloroquine achieves a very high concentration within the ported into the cell by a cytosine permease; a cytosine deam- food vacuole of the parasite and this greatly aids its activity.
inase then converts flucytosine to 5-fluorouracil, which is However, quinine and mefloquine are not concentrated to the incorporated into RNA in place of uracil, leading to the for- same extent, and have much less effect on heme polymeriza- mation of abnormal proteins. There is also an effect on DNA tion, raising the possibility that other (possibly multiple) targets synthesis through inhibition of thymidylate synthetase.35 are involved in the action of these compounds.37,38 8-Aminoquinolines like primaquine, which, at therapeuti- cally useful concentrations exhibit selective activity against liver-stage parasites and gametocytes, possibly inhibit mito-chondrial enzyme systems after undergoing hepatic metabo- The antidermatophyte antibiotic griseofulvin binds to the lism. However, the precise mechanism of action is unknown.
microtubules of the mitotic spindle, interfering with theirassembly and function. However, the precise mechanism of Artemisinin
action and the basis of the selectivity remain to be elucidated.
Artemisinin, the active principle of the Chinese herbal remedyqinghaosu, has several effects on malaria parasites, but the activity appears to be due chiefly to the reactivity of theendoperoxide bridge. This is cleaved in the presence of heme The actions of some antiprotozoal drugs overlap with, or are or free iron within the parasitized red cell to form a short-lived, analogous to, those seen with the antibacterial and antifungal but highly reactive, free radical that irreversibly alkylates agents already discussed. Thus, the activity of 5-nitroimida- zoles such as metronidazole extends to those protozoa thatexhibit an essentially anaerobic metabolism; the antimalarial Atovaquone
agents pyrimethamine and cycloguanil (the metabolic productof proguanil), like trimethoprim, inhibit dihydrofolate reduc- The hydroxynaphthoquinone atovaquone, which exhibits anti- tase; some polyenes and antifungal imidazoles display suffi- malarial and antipneumocystis activity, is an electron transport cient activity against Leishmania and certain other protozoa for inhibitor that causes depletion of the ATP pool. The primary them to have received attention as potential therapeutic agents.
effect is on the iron flavoprotein dihydro-orotate dehydroge- There seems to be deep uncertainty about how other nase, an essential enzyme in the production of pyrimidines.
antiprotozoal agents actually work. Various sites of action have Mammalian cells are able to avoid undue toxicity by use of been ascribed to many of them and, with a few notable excep- preformed pyrimidines.40 Dihydro-orotate dehydrogenase from tions, the literature reveals only desultory attempts to pin down Plasmodium falciparum is inhibited by concentrations of ato- vaquone that are very much lower than those needed to inhibitthe pneumocystis enzyme, raising the possibility that theantimicrobial consequences might differ in the two organ- Quinoline antimalarials
Quinine and the various quinoline antimalarials were oncethought to achieve their effect by intercalation with plasmodi- Arsenical compounds, which are still the mainstay of treatment al DNA after concentration in parasitized erythrocytes.
of African sleeping sickness, poison the cell by an effect on However, these effects occur only at concentrations in excess glucose catabolism and are consequently very toxic to the host.
of those achieved in vivo; moreover, a non-specific effect on The mechanism by which this is achieved and the basis for any DNA does not explain the selective action of these compounds selective action are not well understood, though they are at precise points in the plasmodial life cycle, or the differential known to bind to essential thiol groups. The primary target activity of antimalarial quinolines.
may be trypanothione, which substitutes for glutathione in try- Clarification of the mode of action of these compounds has panosomes, and this may aid the selective toxicity.42 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 21 The actions of other agents with antitrypanosomal activity, and binding to tubulin, the structural protein of micro- including suramin and pentamidine, are also poorly charac- terized.43 Various cell processes, mainly those involved in gly- The basis of the activity of the antifilarial drug diethylcar- colysis within the specialized glycosomes of protozoa of the bamazine has long been a puzzle, since the drug has no effect trypanosome family, have been implicated in the action of on microfilaria in vitro. Consequently it seems likely that the suramin.44 Pentamidine and other diamidines disrupt the try- effect of drug observed in vivo is due to alterations in the panosomal kinetoplast, a specialized DNA-containing surface coat, making them responsive to immunological organelle, probably by binding to DNA, though they also inter- processes from which they are normally protected.55 The source of its effect on adult filarial worms is unknown.
Laboratory studies of leishmania are hampered by the fact that in-vitro culture yields promastigotes that are morpholog-ically and metabolically different from the amastigotes involved in disease. Such evidence as is available suggests that the pen-tavalent antimonials commonly used for treatment inhibit gly- The prospects for the development of selectively toxic antivi- colysis in leishmanial glycosomes. Antifungal azoles take ral agents were long thought to be poor, since the life cycle of advantage of similarities in sterol biosynthesis among fungi and the virus is so closely bound to normal cellular processes.
However, closer scrutiny of the relationship of the virus to the Eflornithine (difluoromethylornithine) is a selective inhibitor cell reveals several points at which the viral cycle might be of ornithine decarboxylase and achieves its effect by depleting the biosynthesis of polyamines such as spermidine, a precur- ● Adsorption to and penetration of the cell.
sor of trypanothione.47 The corresponding mammalian enzyme ● Uncoating of the viral nucleic acid.
has a much shorter half-life than its trypanosomal counterpart, ● The various stages of nucleic acid replication.
and this may account for the apparent selectivity of action. The ● Assembly of the new viral particles.
preferential activity against Trypanosoma brucei gambiense rather ● Release of infectious virions (if the cell is not destroyed).
than the related rhodesiense form may be due to reduced druguptake or differences in polyamine metabolism in the lattersubspecies.48 Several of the drugs used in amebiasis, including the plant alkaloid emetine and diloxanide furoate appear to interfere withprotein synthesis within amebic trophozoites or cysts.49 In the event, it is the process of viral replication (which isextremely rapid relative to most mammalian cells) that hasproved to be the most vulnerable point of attack, and most clinically useful antiviral agents are nucleoside analogs.
Among these, only aciclovir (acycloguanosine) and penci- Just as the cell wall of bacteria is a prime target for selective clovir (the active product of the oral agent famciclovir) exhibit agents and the cell membrane is peculiarly vulnerable in a genuine selectivity. In order to achieve their antiviral effect, fungi, so the neuromuscular system appears to be the nucleoside analogs have to be converted within the cell to the Achilles’ heel of parasitic worms. Despite the fact that present triphosphate derivative. In the case of aciclovir and penci- understanding of the neurobiology of helminths is extremely clovir the initial phosphorylation, yielding aciclovir or penci- meagre, a considerable number of anthelmintic agents have clovir monophosphate, is accomplished by a thymidine kinase been shown to work by paralysing the neuromusculature in coded for by the virus itself. The corresponding cellular various ways. Such compounds include piperazine, prazi- thymidine kinase phosphorylates these compounds very inef- quantel, levamisole, pyrantel pamoate, ivermectin, metri- ficiently and consequently only cells harbouring the virus are fonate (trichlorfon) and dichlorovos.50–52 affected. Moreover, the triphosphates of aciclovir and penci- induces schistosomes to disengage from their intravascular clovir inhibit viral DNA polymerase more efficiently than the attachment site and migrate to the liver, but there is also a cellular enzyme; this is another feature of their selective activ- profound effect on schistosome metabolism and disruption of ity. As well as inhibiting viral DNA polymerase, aciclovir and the tegument, causing exposure of parasite antigens. All these penciclovir triphosphates are incorporated into the growing effects appear to be referable to alterations in calcium home- DNA chain and cause premature termination of DNA syn- A notable exception to the general rule that anthelmintic Other nucleoside analogues, including the anti-HIV agents agents act on the neuromuscular systems of worms is provid- zidovudine, didanosine, zalcitabine, stavudine, lamivudine and ed by the benzimidazole derivatives, including mebendazole abacavir, and the anti-cytomegalovirus agents ganciclovir and and albendazole. These broad-spectrum anthelmintic drugs valganciclovir, act in a non-specific manner because they are seem to have at least two effects on adult worms and larvae: phosphorylated by cellular enzymes and/or are less selective inhibition of the uptake of the chief energy source, glucose; for viral versus host cell enzymes. Ribavirin is also a nucleo- 02-Finch-ch2-pp 20/5/2002 12:50 pm Page 22 C H A P T E R 2 M O D E S O F A C T I O N side analog that acts through the inosine monophosphate pathway. The anti-HIV compounds are thought to act pri-marily to inhibit reverse transcriptase activity by causing pre- The anti-influenza A compound amantadine and its close rel- mature chain termination during the transcription of DNA ative rimantadine appear to act at the stage of viral uptake by from the single-stranded RNA template. Similarly, ganciclovir preventing membrane fusion; these compounds also interfere acts as a chain terminator and DNA polymerase inhibitor with virus disassembly. Both effects may be due to specific during the transcription of cytomegalovirus DNA. Since these interaction of the drugs with a membrane-associated protein compounds lack a hydroxyl group on the deoxyribose ring, they are unable to form phosphodiester linkages in the DNAchain.57 Ribavirin, in contrast, allows DNA synthesis to occur,but prevents the formation of viral proteins, probably by inter- fering with capping of viral mRNA.58 In vitro, ribavirin antag-onizes the action of zidovudine, probably by feedback Two drugs target the neuraminidase of influenza A and B inhibition of thymidine kinase so that the zidovudine is not viruses: zanamivir and oseltamivir. Both directly bind to the neuraminidase enzyme and prevent the formation of infectiousprogeny virions.64–66 NON-NUCLEOSIDE REVERSETRANSCRIPTASE INHIBITORS Although they are structurally unrelated, the non-nucleoside Fomivirsen is the only licensed antisense oligonucleotide for reverse transcriptase inhibitors nevirapine, delavirdine, and the treatment of cytomegalovirus retinitis.67 The nucleotide efavirenz (p. 000) all bind to HIV-1 reverse transcriptase in a sequence of fomivirsen is complementary to a sequence in the messenger RNA transcript of the major immediate early region2 of cytomegalovirus, which is essential for production of infec-tious virus. The binding is reversible.
An alternative tactic to disable HIV is to inhibit the enzyme Further Information
that cleaves the polypeptide precursor of several essential viralproteins.60 Such protease inhibitors in therapeutic use include Detailed information on the mode of action of anti-infective agents can be found saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and Campbell WC, Few RS (eds) 1986 Chemotherapy of parasitic disease. Plenum, New lopinavir/ritonavir (see Chapter 00).
Dax SL 1997 Antibacterial chemotherapeutic agents. Blackie Academic, LondonFranklin TJ, Snow GA 1998 Biochemistry and molecular biology of antimicrobial action, 5th edn. Kluwer Academic Publishers, Dordrecht Frayha GJ, Smyth JD, Gobert JG, Savel J 1997 The mechanism of action of antipro- tozoal and anthelmintic drugs in man. General Pharmacology 28: 273–299 One nucleotide analog is licensed for the treatment of Gale EF, Cundliffe E, Reynolds PE, Richmond MH, Waring MJ 1981 The molecular cytomegalovirus disease in AIDS patients: hydrox- basis of antibiotic action, 2nd edn. Wiley, Chichester Greenwood D, O’Grady F (eds) 1985 The scientific basis of antimicrobial chemo- ypropoxymethyl cytosine (cidofovir). It is phosphorylated by therapy. Cambridge University Press, Cambridge cellular kinases to the triphosphate derivative, which then James DH, Gilles HM 1985 Human antiparasitic drugs: Pharmacology and usage.
becomes a competitive inhibitor of DNA polymerase.
Lancini G, Parenti F, Gallo G-C 1995 Antibiotics: a multidisciplinary approach.
Russell AD, Chopra I 1996 Understanding antibacterial action and resistance, 2nd Scholar EM, Pratt WB 2000 The antimicrobial drugs 2nd edn. Oxford University The simple phosphonoformate salt foscarnet and its close Williams RAD, Lambert PA, Singleton P 1996 Antimicrobial drug action. bios analog phosphonoacetic acid inhibit DNA polymerase activi- ty of herpes viruses by preventing pyrophosphate exchange.61The action is selective in that the corresponding mammalianpolymerase is much less susceptible to inhibition. Activity of References
foscarnet against HIV seems to be due to a different mecha-nism. Like the nucleoside analogs, it inhibits reverse tran- 1. Hancock REW, Bellido F 1992 Antibiotic uptake: unusual results for unusual scriptase activity of retroviruses, but it binds to the enzyme at molecules. Journal of Antimicrobial Chemotherapy 29: 235–239.
a site distinct from that of the nucleoside triphosphates. The effect is non-competitive and reversible.
02-Finch-ch2-pp 20/5/2002 12:50 pm Page 23 29. Ghannoum MA, Rice LB 1999 Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.
4. Arthur M, Reynolds PE, Depardieu F et al 1993 Mechanisms of glycopeptide Clinical Microbiology Reviews 12: 501–517.
resistance in enterococci. Journal of Infection 32: 11–16.
30. Borgers M 1985 Antifungal azole derivatives. In: Greenwood D, O’Grady F (eds) 5. Greenwood D, O’Grady F 1973 The two sites of penicillin action in Escherichia The scientific basis of antimicrobial chemotherapy. Cambridge University coli. Journal of Infectious Diseases 128: 791–794.
6. Handwerger S, Tomasz A 1985 Antibiotic tolerance among clinical isolates of 31. Fromtling RA 1988 Overview of medically important antifungal azole deriva- bacteria. Reviews of Infectious Diseases 7: 368–386.
tives. Clinical Microbiology Reviews 1: 187–217.
32. Stütz A 1990 Allylamine derivatives – inhibitors of fungal squalene epoxidase.
In: Borowski E, Shugar D (eds) Molecular aspects of chemotherapy. Pergamon,New York, p. 205–213 33. Ryder NS 1989 The mode of action of terbinafine. Clinical and Experimental 34. Georgopapadakou NH 2001 Update on antifungals targeted to the cell wall: 9. Chopra I, Hawkey PM, Hinton M 1992 Tetracyclines, molecular and clinical focus on beta-1,3-glucan synthase inhibitors. Expert Opinion in Investigational aspects. Journal of Antimicrobial Chemotherapy 29: 245–277 10. Tai PC, Davis BD 1985 The actions of antibiotics on the ribosome. In: 35. Odds FC 1988 Candida and candidosis. Baillière Tindall, London, p. 305–306.
Greenwood D, O’Grady F (eds) The scientific basis of antimicrobial chemo- 36. Slater AFG, Cerami A 1992 Inhibition by chloroquine of a novel haem poly- therapy. Cambridge University Press, Cambridge, p. 41–68 merase enzyme activity in malaria trophozoites. Nature 355: 167–169 11. Davis BD 1988 The lethal action of aminoglycosides. Journal of Antimicrobial 37. Foote SJ, Cowman AF 1994 The mode of action and the mechanism of resis- tance to antimalarial drugs. Acta Tropica 56: 157–171.
12. Davis BD 1987 Mechanism of bactericidal action of aminoglycosides.
38. Foley M, Tilley L 1998 Quinoline antimalarials: mechanisms of action and resis- tance and prospects for new agents. Pharmacology and Therapeutics 79: 13. Cocito C, Di Giambattista M, Nyssen E, Vannuffel P 1997 Inhibition of protein synthesis by streptogramins and related antibiotics. Journal of Antimicrobial 39. Meshnick SR, Taylor TE, Kamchonwongpaison S 1996 Artemisinin and the anti- malarial endoperoxides: from herbal remedy to targeted chemotherapy.
14. Vannuffel P, Cocito C 1996 Mechanism of action of streptogramins and 40. Artymowicz RJ, James VE 1993 Atovaquone: a new antipneumocystis agent.
15. Shinabarger DL, Marotti KR, Murray RW et al 1997 Mechanism of action of oxa- zolidinones: effect of linezolid and eperezolid on translation reactions.
41. Ittarat I, Asawamahasakada W, Bartlett MS, Smith JW, Meshnick SR 1995 Effects Antimicrobial Agents and Chemotherapy 41: 2132–2136 of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate 16. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL 1998 The oxazolidinone line- dehydrogenase. Antimicrobial Agents and Chemotherapy 39: 325–328.
zolid inhibits initiation of protein synthesis in bacteria. Antimicrobial Agents 43. Denise H, Barrett MP 2001 Uptake and mode of action of drugs used against 17. Lin AH, Murray RW, Vidmar TJ, Marotti KR 1997 The oxazolidinone eperezolid sleeping sickness. Biochemical Pharmacology 61: 1–5.
binds to the 50S ribosomal subunit and competes with binding of chloram- 44. Voogd TE, Vansterkenburg ELM, Wilting J, Janssen LHM 1993 Recent research phenicol and lincomycin. Antimicrobial Agents and Chemotherapy 41: on the biological activity of suramin. Pharmacological Reviews 45: 177–203 45. Sands M, Kron MA, Brown RB 1985 Pentamidine: a review. Reviews of 18. Parenti MA, Hatfield SM, Leyden JJ 1987 Mupirocin: a topical antibiotic with a unique structure and mode of action. Clinical Pharmacology 6: 761–770 46. Berman JD 1988 Chemotherapy for leishmaniasis: biochemical mechanisms, 19. Yanagisawa T, Lee JT, Wu HC, Kawakami M 1994 Relationship of protein struc- clinical efficacy and future strategies. Clinical Infectious Diseases 10: 560–586 ture of isoleucyl-tRNA synthetase with pseudomonic acid resistance of 47. McCann PP, Bacchi CJ, Clarkson AB et al 1986 Inhibition of polyamine biosyn- Escherichia coli. A proposed mode of action of pseudomonic acid as an thesis by a-difluoromethylornithine in African trypanosomes and inhibitor of isoleucyl-tRNA synthetase. Journal of Biological Chemistry 269: Pneumocystis carinii as a basis for chemotherapy: biochemical and clinical aspects. American Journal of Tropical Medicine and Hygiene 35: 1153–1156 48. Bacchi CJ 1993 Resistance to clinical drugs in African trypanosomes 21. Ng EYW, Trucksis M, Hooper DC 1996 Quinolone resistance mutations in topoi- 49. Khaw M, Panosian CB 1995 Human antiprotozoal therapy: past, present and somerase IV: relationship to the flqA locus and genetic evidence that topoiso- future. Clinical Microbiology Reviews 8: 427–439.
merase IV is the primary target and DNA gyrase is the secondary target of 50. Fisher MH, Mrozik H 1992 The chemistry and pharmacology of avermectins.
fluoroquinolones in Staphylococcus aureus. Antimicrobial Agents and Annual Review of Pharmacology and Toxicology 32: 537–553.
51. Geary TG, Klein RD, Vanover L, Bowman JW, Thompson DP 1992 The nervous 22. Edwards DI 1993 Nitroimidazole drugs – action and resistance mechanisms. I.
systems of helminths as targets for drugs. Journal of Parasitology 78: 215–230.
Mechanisms of action. Journal of Antimicrobial Chemotherapy 31: 9–20.
52. Rosenblatt JE 1992 Antiparasitic agents. Mayo Clinic Proceedings 67: 276–287 23. Goodwin A, Kersulyte D, Sisson G et al 1998 Metronidazole resistance in 53. Day TA, Bennett JL, Pax RA 1992 Praziquantel: the enigmatic antiparasitic.
Helicobacter pylori is due to null mutations in a gene (rdxA) that encodes the oxygen-insensitive NADPH nitroreductase. Molecular Microbiology 28: 54. Lacey E 1990 The mode of action of benzimidazoles. Parasitology Today 6: 24. McOsker CC, Fitzpatrick PM 1994 Nitrofurantoin: mechanism of action and 55. Hawking F 1981 Chemotherapy for filariasis. Antibiotics and Chemotherapy 30: implications for resistance development in common uropathogens. Journal of Antimicrobial Chemotherapy 33 (Suppl. A): 23–30 56. Crumpacker CS 1989 Molecular targets of antiviral therapy. New England 25. Gilleland HE, Champlin FR, Conrad RS 1984 Chemical alterations in cell envelopes of Pseudomonas aeruginosa upon exposure to polymyxin: a poss- 57. Lipsky JJ 1993 Zalcitabine and didanosine. Lancet 341: 30–32 ible mechanism to explain adaptive resistance to polymyxin. Canadian Journal 58. Hall CB 1987 Ribavirin. In: Peterson PK, Verhoef J (eds) The antimicrobial agents annual – 2. Elsevier, Amsterdam, p. 351–362.
26. Boman HG, Marsh J, Goode JA (eds) 1994 Antimicrobial peptides. Ciba 59. Vogt MW, Hartshom KL, Furman PA et al 1987 Ribavirin antagonizes the effect Foundation Symposium 186. Wiley, Chichester of azidothymidine on HIV replication. Science 235: 1376–1379 27. Boman HG 2000 Innate immunity and the normal microflora. Immunological 60. Debouck C 1992 The HIV-1 protease as a therapeutic target for AIDS. AIDS Research and Human Retroviruses 8: 153–164.
28. Elewski BE 1993 Mechanisms of action of systemic antifungal agents. Journal 61. Crumpacker CS 1992 Mechanism of action of foscarnet against viral poly- of the American Academy of Dermatology 28: S28–S34.
merases. American Journal of Medicine 92 (Suppl. 2A): 2A-35–2A–75.
02-Finch-ch2-pp 20/5/2002 12:50 pm Page 24 C H A P T E R 2 M O D E S O F A C T I O N 62. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH 1985 The molecular basis of the and 5-guanidino-3, 4-dehydro-N-(2-ethylbutyrul)-3-piperideinecarboxylic specific anti-influenza action of amantadine. EMBO Journal 4: 3021–3024 acids related to zanamivir and oseltamivir, inhibitors of influenza virus neu- 63. Skehel JJ 1992 Amantadine blocks the channel. Nature 358: 110–111 raminidases. Organic Letters 2: 3837–3840 64. Waghorn SL, Goa KL 1998 Zanamivir. Drugs 55: 721–725 67. Perry CM, Balfour JA 1999 Fomivirsen. Drugs 57: 375–380 65. Bardsley-Elliot A, Noble S 1999 Oseltamivir Drugs 58: 851–860 Hooper DC 1993 Quinolone mode of action Drugs 49 (Suppl. 2): 10–15.
66. Shitara E, Nishimura Y, Nerome K et al 2000 Synthesis of 6-acetamido-5-amino-

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