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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.

ABSTRACT: Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II 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.

SUBMITTER: Kim P

PROVIDER: S-EPMC1462948 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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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 P Zhang Yong-Mei YM Shenoy Gautham G Nguyen Quynh-Anh QA Boshoff Helena I HI Manjunatha Ujjini H UH Goodwin Michael B MB Lonsdale John J Price Allen C AC Miller Darcie J DJ Duncan Ken K White Stephen W SW Rock Charles O CO Barry Clifton E CE Dowd Cynthia S CS

Journal of medicinal chemistry 20060101 1

Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II 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 suc ...[more]

PMID: 16392800

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Project description:Oxidative damage to 5-methylcytosine in DNA, followed by deamination, yields thymine glycol (Tg), 5,6-dihydroxy-5,6-dihydrothymine, mispaired with deoxyguanosine. The structure of the 5R Tg.G mismatch pair has been refined using a combination of simulated annealing and isothermal molecular dynamics calculations restrained by NMR-derived distance restraints and torsion angle restraints in 5'-d(G(1)T(2)G(3)C(4)G(5)Tg(6)G(7)T(8)T(9)T(10)G(11)T(12))-3'.5'-d(A(13)C(14)A(15)A(16)A(17)C(18)G(19)C(20)G(21)C(22)A(23)C(24))-3'; Tg = 5R Tg. In this duplex the cis-5R,6S:trans-5R,6R equilibrium favors the cis-5R,6S epimer [Brown, K. L., Adams, T., Jasti, V. P., Basu, A. K., and Stone, M. P. (2008) J. Am. Chem. Soc. 130, 11701-11710]. The cis-5R,6S Tg lesion is in the wobble orientation such that Tg(6) O(2) is proximate to G(19) N1H and Tg(6) N3H is proximate to G(19) O(6). Both Tg(6) and the mismatched nucleotide G(19) remain stacked in the helix. The Tg(6) nucleotide shifts toward the major groove and stacks below the 5'-neighbor base G(5), while its complement G(19) stacks below the 5'-neighbor C(20). In the 3'-direction, stacking between Tg(6) and the G(7).C(18) base pair is disrupted. The solvent-accessible surface area of the Tg nucleotide increases as compared to the native Watson-Crick hydrogen-bonded T.A base pair. An increase in T(2) relaxation rates for the Tg(6) base protons is attributed to puckering of the Tg base, accompanied by increased disorder at the Tg.G mismatch pair. The axial vs equatorial conformation of the Tg(6) CH(3) group cannot be determined with certainty from the NMR data. The rMD trajectories suggest that in either the axial or equatorial conformations the cis-5R,6S Tg lesion does not form strong intrastrand hydrogen bonds with the imidazole N7 atom of the 3'-neighbor purine G(7). The wobble pairing and disorder of the Tg.G mismatch correlate with the reduced thermodynamic stability of the mismatch and likely modulate its recognition by DNA base excision repair systems.

Dataset Information

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.

Publications

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.

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