Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli

Pilho Kim, Yong Mei Zhang, Gautham Shenoy, Quynh Anh Nguyen, Helena I. Boshoff, Ujjini H. Manjunatha, Michael B. Goodwill, John Lonsdale, Allen C. Price, Darcie J. Miller, Ken Duncan, Stephen W. White, Charles O. Rock, Clifton E. Barry, Cynthia S. Dowd

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Thiolactomycin inhibits bacterial cell growth through inhibition of the β-ketoacyl-ACP synthase activity of type 11 fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC 50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.

Original languageEnglish
Pages (from-to)159-171
Number of pages13
JournalJournal of Medicinal Chemistry
Volume49
Issue number1
DOIs
Publication statusPublished - 12-01-2006

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Structure-Activity Relationship
Mycobacterium tuberculosis
Catalytic Domain
Escherichia coli
Fatty Acid Synthases
Terpenes
Enzyme Assays
Enzymes
Growth
thiolactomycin
isoprene

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Kim, Pilho ; Zhang, Yong Mei ; Shenoy, Gautham ; Nguyen, Quynh Anh ; Boshoff, Helena I. ; Manjunatha, Ujjini H. ; Goodwill, Michael B. ; Lonsdale, John ; Price, Allen C. ; Miller, Darcie J. ; Duncan, Ken ; White, Stephen W. ; Rock, Charles O. ; Barry, Clifton E. ; Dowd, Cynthia S. / Structure-activity relationships at the 5-position of thiolactomycin : An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 1. pp. 159-171.
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abstract = "Thiolactomycin inhibits bacterial cell growth through inhibition of the β-ketoacyl-ACP synthase activity of type 11 fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC 50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.",
author = "Pilho Kim and Zhang, {Yong Mei} and Gautham Shenoy and Nguyen, {Quynh Anh} and Boshoff, {Helena I.} and Manjunatha, {Ujjini H.} and Goodwill, {Michael B.} and John Lonsdale and Price, {Allen C.} and Miller, {Darcie J.} and Ken Duncan and White, {Stephen W.} and Rock, {Charles O.} and Barry, {Clifton E.} and Dowd, {Cynthia S.}",
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Kim, P, Zhang, YM, Shenoy, G, Nguyen, QA, Boshoff, HI, Manjunatha, UH, Goodwill, MB, Lonsdale, J, Price, AC, Miller, DJ, Duncan, K, White, SW, Rock, CO, Barry, CE & Dowd, CS 2006, 'Structure-activity relationships at the 5-position of thiolactomycin: An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli', Journal of Medicinal Chemistry, vol. 49, no. 1, pp. 159-171. https://doi.org/10.1021/jm050825p

Structure-activity relationships at the 5-position of thiolactomycin : An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli. / Kim, Pilho; Zhang, Yong Mei; Shenoy, Gautham; Nguyen, Quynh Anh; Boshoff, Helena I.; Manjunatha, Ujjini H.; Goodwill, Michael B.; Lonsdale, John; Price, Allen C.; Miller, Darcie J.; Duncan, Ken; White, Stephen W.; Rock, Charles O.; Barry, Clifton E.; Dowd, Cynthia S.

In: Journal of Medicinal Chemistry, Vol. 49, No. 1, 12.01.2006, p. 159-171.

Research output: Contribution to journalArticle

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T1 - Structure-activity relationships at the 5-position of thiolactomycin

T2 - An intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli

AU - Kim, Pilho

AU - Zhang, Yong Mei

AU - Shenoy, Gautham

AU - Nguyen, Quynh Anh

AU - Boshoff, Helena I.

AU - Manjunatha, Ujjini H.

AU - Goodwill, Michael B.

AU - Lonsdale, John

AU - Price, Allen C.

AU - Miller, Darcie J.

AU - Duncan, Ken

AU - White, Stephen W.

AU - Rock, Charles O.

AU - Barry, Clifton E.

AU - Dowd, Cynthia S.

PY - 2006/1/12

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N2 - Thiolactomycin inhibits bacterial cell growth through inhibition of the β-ketoacyl-ACP synthase activity of type 11 fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC 50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.

AB - Thiolactomycin inhibits bacterial cell growth through inhibition of the β-ketoacyl-ACP synthase activity of type 11 fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC 50 and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.

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