Journal
AMINO ACIDS
Volume 42, Issue 6, Pages 2283-2291Publisher
SPRINGER
DOI: 10.1007/s00726-011-0970-7
Keywords
Amino acid metabolism; Antibiotics; P5C reductase; Proline; Streptococcus sp
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Funding
- University of Ferrara [FAR2009-2010]
- Spinner Consortium, Emilia Romagna Region [626/09]
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Compounds able to interfere with amino acid biosynthesis have the potential to inhibit cell growth. In both prokaryotic and eukaryotic microorganisms, unless an ornithine cyclodeaminase is present, the activity of delta(1)-pyrroline-5-carboxylate (P5C) reductase is mandatory to proline production, and the enzyme inhibition should result in amino acid starvation, blocking in turn protein synthesis. The ability of some substituted derivatives of aminomethylenebisphosphonic acid and its analogues to interfere with the activity of the enzyme from the human pathogen was investigated. Several compounds were able to suppress activity in the micromolar range of concentrations, with a mechanism of uncompetitive type with respect to the substrate P5C and non-competitive with respect to the electron donor NAD(P)H. The actual occurrence of enzyme inhibition in vivo was supported by the effects of the most active derivatives upon bacterial growth and free amino acid content.
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