Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth

ChemMedChem - Tập 11 Số 19 - Trang 2205-2215 - 2016
Janish Desai1,2, Yang Wang3,2, Ke Wang3, Satish R. Malwal3, Eric Oldfield1,3
1Center for Biophysics and Quantitative Biology University of Illinois at Urbana–Champaign 1110 West Green Street Urbana IL 61801 USA
2these authors contributed equally to this work
3Department of Chemistry University of Illinois at Urbana–Champaign 600 South Mathews Avenue Urbana IL 61801 USA

Tóm tắt

AbstractWe synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron‐withdrawing aryl‐alkyl side chains which inhibited the growth of Gram‐negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1–4 μg mL−1 levels. They were found to be potent inhibitors of FPPS; cell growth was partially “rescued” by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2–6 μg mL−1) against Gram‐positive but not Gram‐negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1–2 μg mL−1.

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ChemMedChem

Tập 11 Số 19

2205-2215

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