Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes

Welch, KT
Virga, KG
Whittemore, NA
Özen, Can
Wright, E
Brown, CL
Lee, RE
Serpersu, EH
Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine pharmacophore shared by all aminoglycoside antibiotics that contain the 2-deoxystreptamine ring. A discovery library of molecules was prepared by attaching different side chains to both sides of the 1,3-diamine motif. Several of these diamines showed inhibitory activity toward two or three different representative aminoglycoside-modifying enzymes (AGMEs). These studies yielded the first non-carbohydrate inhibitor N-cyclohexyl-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound G,H) that is competitive with respect to the aminoglycoside binding to the enzyme aminoglycoside-2 ''-nucleotidyltransferase-la (ANT(2 '')). Another diamine molecule N-[2-(3,4-dimethoxyphenyl)-ethyl]-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound H,I) was shown to be a competitive inhibitor of two separate enzymes (aminoglycoside-3'-phosphotransferase-IIIa (APH(3')) and ANT(2 '')) with respect to metal-ATP. Thermodynamic and structural-binding properties of the complexes of APH(3') with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.


Studies of enzymes that cause resistance to aminoglycosides antibiotics.
Serpersu, Engin H; Özen, Can; Wright, Edward (2008-01-01)
Aminoglycoside antibiotics are highly potent, wide-spectrum bactericidals (1, 2). Bacterial resistance to aminoglycosides, however, is a major problem in the clinical use of aminoglycosides. Enzymatic modification of aminoglycosides is the most frequent resistance mode among several resistance mechanisms employed by resistant pathogens (1,3). Three families of aminoglycoside modifying enzymes, O-phosphotransferases, N-acetyltransferases, and N-nucleotidyltransferases, are known to have more than 50 enzymes ...
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Some yeasts secrete polypeptide toxins, which are lethal to other sensitive yeast cells, gram-positive pathogenic bacteria and pathogenic fungi. Therefore these are designated as killer toxins. Killer toxins are suggested as potent antimicrobial agents especially for the protection of fermentation process against contaminating yeasts, biological control of undesirable yeasts in the preservation of foods. Moreover they are promising antimicrobial agents in the medical field; due to immune system suppressing ...
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Akaysoy, Sergen; Özcengiz, Gülay; Department of Biology (2022-9-15)
Bacillus subtilis is the Gram-positive model bacterium that enzymatically produces the dipeptide antibiotic bacilysin. Bacilysin is the simplest bioactive peptide known composed of L-alanine at its N-terminal and L-anticapsin at its C-terminal. In a former work in our laboratory, a mutant strain of B. subtilis, namely OGU1 was constructed by bacA-targeted pMutin T3 insertion into the parental strain PY79 genome resulting in a genomic organization bacA′::lacZ::erm::bacABCDEF and unable to synthesize bacilysi...
Citation Formats
K. Welch et al., “Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes,” BIOORGANIC & MEDICINAL CHEMISTRY, pp. 6252–6263, 2005, Accessed: 00, 2020. [Online]. Available: