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Analogues of thiolactomycin: potential drugs with enhanced anti-mycobacterial activity^a

Department of Chemistry, University of Newcastle, Newcastle-upon-Tyne NE1 7RU, UK¹
School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK²
GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK³
Department of Microbiology, Colorado State University, Fort Collins, CO 80523-1677, USA⁴

Author for correspondence: David E. Minnikin. Tel: +44 121 415 8126. Fax: +44 121 414 5925. e-mail: d.e.minnikin{at}bham.ac.uk

Analogues of the antibiotic thiolactomycin (TLM) have been synthesized and have been shown to have enhanced activity against whole cells of Mycobacterium tuberculosis H37Rv and against mycolic acid biosynthesis in cell extracts of Mycobacterium smegmatis. TLM has a methyl-branched butadienyl side chain attached at position 5 on a ‘thiolactone’ ring, namely 4-hydroxy-3,5-dimethyl-5H-thiophen-2-one. Various combinations of strong bases were explored to create a reactive anion at position 5 on the thiolactone ring which could react with halides to produce 5-substituted derivatives; the best reagent was two equivalents of lithium-bis-(trimethylsilyl)amide in tetrahydrofuran. The analogue with a 5-tetrahydrogeranyl substituent showed the best biological activity with an MIC₉₀ for M. tuberculosis of 29 µM and 92% mycolate inhibition in extracts of M. smegmatis, as compared to 125 µM and 54%, respectively, for TLM; other related C₁₀ and C₁₅ isoprenoid derivatives had similar biological activity. These isoprenoid-based derivatives did not inhibit type II fatty acid synthase from M. smegmatis, but compounds with iso-butyl and iso-butenyl side chains did show some inhibitory activity against this enzyme. These short-chain derivatives did not inhibit mycolate synthesis or have significant antibiotic activity. Treatment of the thiolactone with a weaker base, sodium hydride in tetrahydrofuran, gave 3-alkyl-3,5-dimethyl-thiophene-2,4-dione analogues, which had no effect on fatty acid or mycolate synthesis. However, the geranyl derivative had an MIC₉₉ of 60 µM for M. tuberculosis, one quarter that (240 µM) of TLM, demonstrating its excellent antibiotic potential against an unknown cellular target.

Keywords: mycobacteria, mycolic acids, antibiotics, tuberculosis

Abbreviations: cap film, capillary film; EI, electron impact; FAME, fatty acid methyl ester; FAS-I, type I fatty acid synthase; FAS-II, type II fatty acid synthase; MAME, mycolic acid methyl ester; THF, tetrahydrofuran; TLM, thiolactomycin

^a Details for the preparation of the thiolactomycin analogues shown in Table 1 are available as supplementary data in Microbiology Online (http://mic.sgmjournals.org).

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