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. 2008 Feb 15;18(4):1507-10.
doi: 10.1016/j.bmcl.2007.12.061. Epub 2007 Dec 27.

Synthesis of and evaluation of lipid A modification by 4-substituted 4-deoxy arabinose analogs as potential inhibitors of bacterial polymyxin resistance

T Kline  1 , M S Trent, C M Stead, M S Lee, M C Sousa, H B Felise, H V Nguyen, S I Miller
Affiliations

Synthesis of and evaluation of lipid A modification by 4-substituted 4-deoxy arabinose analogs as potential inhibitors of bacterial polymyxin resistance

T Kline et al. Bioorg Med Chem Lett. .

Abstract

Three sets of novel 4-deoxy-l-arabinose analogs were synthesized and evaluated as potential inhibitors of the bacterial resistance mechanism in which lipid A, on the outer membrane, is modified with 4-amino-4-deoxy-l-arabinose (l-Ara4N). One compound diminished the transfer of l-Ara4N onto lipid A. These results suggest that small molecules might be designed that would effect the same reversal of bacterial resistance observed in genetic knockouts.

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Figures

Figure 1
Figure 1
Figure 2
Figure 2
Assay of PmrK/ArnT aminoarabinose transferase activity. Membranes from S. typhimurium strain JSG435 were assayed for the transfer of L-Ara4N from endogenous sources to the tetra-acylated lipid A precursor 4’-32P-lipid IVA. The protein concentration was 1 mg/ml and the concentration of the inhibitor when present was 1 mM. Assays were carried out as previously described for 0.5 h (Panel A) or for 6 h (Panel B) at 30 C using 5 µM 4’-32P-lipid IVA (20,000 cpm/nmol). The reaction products were separated by thin layer chromatography in the solvent chloroform, pyridine, 88% formic acid, water (50:50:16:5, v/v) and visualized by Phosphorimaging. Lipid IIA arises from the addition of L-Ara4N to the starting substrate lipid IVA. Lipids IIB and IVB arise from the PagP-dependent addition of palmitate to lipid IIA and lipid IVA, respectively. Reaction products modified with L-Ara4N are indicated by an asterisk.
Scheme I
Scheme I
a. (i) 1 M HCl/acetone, then NaHCO3, (ii) 1M HCl, 90 °C, (iii) Li2CO3, (iv)Ac2O, NaOAc, reflux; b. (CH3)2NH, CH3CN, −20 °C; c. (i) 2-chloro-4[H]-benzodioxaphosphorin-4-one, NEt3, THF-dioxane, 0 °C, (ii) H2O; d. (i) Dowex 50W × 8, H+ form, THF-dioxane, (ii) tBuOOH/decane, cat. I2, NEt3; e. (i) tri n-octylalmine/pyridine, (ii) UMP morpholidate, DCCM salt, tetrazole, pyridine
Scheme II
Scheme II
a. (i) n-BuLi, THF, (ii) tetrabenzylpyrophosphate, THF; b. (CH3)3P, pyridine, CH2Cl2; c. (i) H2, Pd-C, CH3OH (ii) NEt3; d. UMP morpholidate, tetrazole, pyridine
Scheme III
Scheme III
a. (i) ethyl benzyl H-phosphinate, BTSTFA, pyridine (ii) 1:3 CH3OH-CHCl3 , Δ; b. (i) H2, Pd-C, CH3OH (ii) NEt3; c. (i) tri-n-octylamine, pyridine, (ii) UMP morpholidate, tetrazole, pyridine
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