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7 Antibiotics and New Inhibitors of the Cell Wall

Authors: Lynn G. Dover1, Luke Alderwick2, Veemal Bhowruth3, Alistair K. Brown4, Laurent Kremer5, Gurdyal S. Besra6
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Affiliations: 1: Biomedical Sciences Division, School of Applied Sciences, Ellison Building, Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom; 2: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; 3: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; 4: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; 5: CNRS UMR 5235, Dynamique des Interactions, Membranaires Normales et Pathologiques, Université de Montpellier II, Case 107, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France; 6: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
Content Type: Monograph
Publication Year: 2008
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Abstract:

A “golden age” of tuberculosis (TB) chemotherapy was heralded by the discovery of streptomycin in 1944. The chemotherapeutic regimen consists of an initial 2-month phase of treatment with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB), followed by a continuation phase of treatment lasting four months with INH and RIF. Important considerations for new agents include enhancement of penetration of infection sites, such as lung cavities, and long biological half-lives; achieving either might represent a significant advance toward shortening therapy and lead to simpler treatment regimens with improved patient compliance. The products of the locus of were identified as the targets for EMB using a strategy of target overexpression. The locus contains three genes, , , and ; the former encodes a putative regulator of and embB and is expendable for the resistant phenotype, which is copy number dependent. Pharmacoproteomic studies with H37Rv revealed that similar protein profiles were catalogued after both EMB and SQ109 treatments. A spontaneous mutant of designated mc651 is resistant to INH, but retains wild-type KatG activity. Analyses of treated sensitive bacteria using electron microscopy revealed dysfunction in cell wall biosynthesis and incomplete septation. The increased abundance of CmaA2, involved in mycolic acid biosynthesis under anaerobic conditions suggests a level of metabolic activity related to mycolic acid biosynthesis under conditions usually associated with a transition to dormancy that may be linked, resulting in modulation of mycolic acid chain length during a dormant or persistent anaerobic state.

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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7 Antibiotics and New Inhibitors of the Cell Wall
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Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
/content/10.1128/9781555815783.ch07.ch07fig01
Figure 1.
Schematic representation of mycolic acid synthesis and its inhibition. De novo fatty acid biosynthesis is carried out by fatty acid synthase (FAS-I), a function that appears to be inhibited by pyrazinoic acid (POA) and analogues. Stearate is transformed to the monounsaturated oleate by the Δ9 desaturase DesA3, the target of ISO or ISO*. Medium-chain-length fatty acyl primers are extended to form meromycolic acid precursors by the enzymes of FAS-II (one of which is likely a target of ISO*). All enzymes and domains of FAS-I are shaded to signify function; from lightest to darkest, these are β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, enoyl-ACP reductase (inhibited by INH/ETH/PTH NAD adducts), β-ketoacyl-ACP synthase (inhibited by TLM and possibly OSA). During elongation, meromycolic acids are variously modified. The methyltransferases responsible are likely the targets for TAC* and PA-824. Drugs: POA, pyrazinoic acid; ISO, isoxyl; ISO*, activated ISO; ETH, ethionamide; PTH, prothionamide; INH, isoniazid; -NAD signifies an adduct with nicotinamide adenine dinucleotide, TAC*, activated thiacetazone; OSA, -octylsulfonylacetamide; TLM, thiolactomycin.
10.1128/9781555815783/f0108-01_thmb.gif
10.1128/9781555815783/f0108-01.gif
Image of Figure 1.
Figure 1.

Schematic representation of mycolic acid synthesis and its inhibition. De novo fatty acid biosynthesis is carried out by fatty acid synthase (FAS-I), a function that appears to be inhibited by pyrazinoic acid (POA) and analogues. Stearate is transformed to the monounsaturated oleate by the Δ9 desaturase DesA3, the target of ISO or ISO*. Medium-chain-length fatty acyl primers are extended to form meromycolic acid precursors by the enzymes of FAS-II (one of which is likely a target of ISO*). All enzymes and domains of FAS-I are shaded to signify function; from lightest to darkest, these are β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, enoyl-ACP reductase (inhibited by INH/ETH/PTH NAD adducts), β-ketoacyl-ACP synthase (inhibited by TLM and possibly OSA). During elongation, meromycolic acids are variously modified. The methyltransferases responsible are likely the targets for TAC* and PA-824. Drugs: POA, pyrazinoic acid; ISO, isoxyl; ISO*, activated ISO; ETH, ethionamide; PTH, prothionamide; INH, isoniazid; -NAD signifies an adduct with nicotinamide adenine dinucleotide, TAC*, activated thiacetazone; OSA, -octylsulfonylacetamide; TLM, thiolactomycin.

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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Figure 2.
Structures of ethambutol and SQ109. Ethambutol inhibits arabinan deposition, whereas SQ109 appears to interfere with lipid biosynthesis.
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Image of Figure 2.
Figure 2.

Structures of ethambutol and SQ109. Ethambutol inhibits arabinan deposition, whereas SQ109 appears to interfere with lipid biosynthesis.

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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Figure 3.
Antimycobacterial prodrug inhibitors of mycolic acid biosynthesis. (A) Formation of isonicotinoyl adducts with isoniazid (INH), ethionamide (ETH), and prothionamide (PTH). INH is peroxidatively activated through the peroxidase activity of KatG and reacts with NAD to form its adduct. ADPR represents adenosine diphosphate ribose. Similar products form after the oxidative activation of ETH by EthA. All three adducts represent tight-binding slow inhibitors of InhA. The adduct depicted is PTH-NAD, which has an extended alkyl branch over ETH-NAD. (B) Structures of the EthA-activable prodrugs isoxyl (ISO) and thiacetazone (TAC).
10.1128/9781555815783/f0112-01_thmb.gif
10.1128/9781555815783/f0112-01.gif
Image of Figure 3.
Figure 3.

Antimycobacterial prodrug inhibitors of mycolic acid biosynthesis. (A) Formation of isonicotinoyl adducts with isoniazid (INH), ethionamide (ETH), and prothionamide (PTH). INH is peroxidatively activated through the peroxidase activity of KatG and reacts with NAD to form its adduct. ADPR represents adenosine diphosphate ribose. Similar products form after the oxidative activation of ETH by EthA. All three adducts represent tight-binding slow inhibitors of InhA. The adduct depicted is PTH-NAD, which has an extended alkyl branch over ETH-NAD. (B) Structures of the EthA-activable prodrugs isoxyl (ISO) and thiacetazone (TAC).

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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Figure 4.
Thiolactomycin may mimic malonyl-ACP in the active site of β-ketoacyl-ACP synthases. The figure illustrates the perceived similarity (shaded area) between the structure of thiolactomycin (TLM) (right) and the thiomalonate moiety of malonyl-ACP (left). The amino acid residues highlighted interact with TLM in its complex with β-ketoacyl-ACP synthase FabB, which is broadly analogous to KasA of . The numerals 3 and 5 indicate carbon atoms through which analogues of TLM have been generated (see text).
10.1128/9781555815783/f0119-01_thmb.gif
10.1128/9781555815783/f0119-01.gif
Image of Figure 4.
Figure 4.

Thiolactomycin may mimic malonyl-ACP in the active site of β-ketoacyl-ACP synthases. The figure illustrates the perceived similarity (shaded area) between the structure of thiolactomycin (TLM) (right) and the thiomalonate moiety of malonyl-ACP (left). The amino acid residues highlighted interact with TLM in its complex with β-ketoacyl-ACP synthase FabB, which is broadly analogous to KasA of . The numerals 3 and 5 indicate carbon atoms through which analogues of TLM have been generated (see text).

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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Figure 5.
Pyrazinamide and analogues, proposed inhibitors of fatty acid synthase (FAS-I). Pyrazinamide (PZA) is deamidated to pyrazinoic acid (POA) through pyrazinamidase (PZase). This processing at least promotes its retention in the cytoplasm but may unmask its toxicity. Pyrazinoic acid esters, represented here by -propyl pyrazinoate (n’PPA) can be hydrolyzed to produce POA. It is not known whether this modification, which presumably could be carried out by a mycobacterial esterase, is required to activate the drug.
10.1128/9781555815783/f0120-01_thmb.gif
10.1128/9781555815783/f0120-01.gif
Image of Figure 5.
Figure 5.

Pyrazinamide and analogues, proposed inhibitors of fatty acid synthase (FAS-I). Pyrazinamide (PZA) is deamidated to pyrazinoic acid (POA) through pyrazinamidase (PZase). This processing at least promotes its retention in the cytoplasm but may unmask its toxicity. Pyrazinoic acid esters, represented here by -propyl pyrazinoate (n’PPA) can be hydrolyzed to produce POA. It is not known whether this modification, which presumably could be carried out by a mycobacterial esterase, is required to activate the drug.

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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Figure 6.
The structures of novel agents targeting mycolic acid biosynthesis. The structures of -octylsulfonylacetamide (OSA) and nitroimidazopyran PA-824, which affect mycolic acid biosynthesis, are illustrated. OSA mimics the proposed transition state (TS) generated during the Claisen-like condensation reaction.
10.1128/9781555815783/f0122-01_thmb.gif
10.1128/9781555815783/f0122-01.gif
Image of Figure 6.
Figure 6.

The structures of novel agents targeting mycolic acid biosynthesis. The structures of -octylsulfonylacetamide (OSA) and nitroimidazopyran PA-824, which affect mycolic acid biosynthesis, are illustrated. OSA mimics the proposed transition state (TS) generated during the Claisen-like condensation reaction.

Citation: Dover L, Alderwick L, Bhowruth V, Brown A, Kremer L, Besra G. 2008. 7 Antibiotics and New Inhibitors of the Cell Wall, p 107-131. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch7
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