Abstract
NMR spectroscopy is a powerful technique for separating and measuring each distinct pKa value of the amino groups around aminoglycoside antibiotics. Unambiguous assignments were made for each individual amine substituent on 2-deoxystreptamine, tobramycin, kanamycin B, amikacin, sisomicin, and netilmicin using variations in the NMR spectroscopic chemical shift (δ) with 1H, 13C, and 15N HMBC; the individual pKa values of netilmicin are reported for the first time.
Highlights
These polyamine-type alkaloids are primarily used for the treatment of infection by Gram-negative or Gram-positive bacteria.[1−5] The target at which these drugs act is found in the 16S fragment of ribosomal RNA located in the 30S subunit of the 70S bacterial ribosome, leading to cell death.[6−8] The amino functional group substituents around the different rings of aminoglycoside antibiotics are key to the biological activities of these natural product alkaloids
1H, 13C, and 15N HMBC nuclear magnetic resonance (NMR) spectroscopy is a powerful technique for the measurement of the individual pKa values
Unambiguous assignments have been made for each amine substituent on tobramycin, kanamycin B, amikacin, sisomicin, and netilmicin using variations in the chemical shift
Summary
Aminoglycosides are clinically important microorganismderived natural products, which consist of an aminocyclitol moiety 2-deoxystreptamine or a streptidine ring in streptomycin attached to amino sugars by glycosidic bonds.[1,2] These polyamine-type alkaloids are primarily used for the treatment of infection by Gram-negative (aerobic) or Gram-positive bacteria.[1−5] The target at which these drugs act is found in the 16S fragment of ribosomal RNA (rRNA) located in the 30S subunit of the 70S bacterial ribosome, leading to cell death.[6−8] The amino functional group substituents around the different rings of aminoglycoside antibiotics are key to the biological activities of these natural product alkaloids. This study is to determine individual pKa values by detailed nuclear magnetic resonance (NMR) spectroscopy of selected aminoglycoside alkaloids from Streptomyces and Micromonospora. Studying the pKa values of the ionizable nitrogen atoms in these antibiotic alkaloids will afford a better understanding of their structure−activity relationships (SAR), especially the order in which these similar functional groups gain/lose protons. Such data will potentially help in understanding the order of target rRNA binding, in bacterial cells, of the key basic functional groups or their conjugate ammonium ions. The aim is to measure pKa values of individual amines on aminoglycosides by using new combinations of 1H, 13C, and 15N HMBC NMR spectroscopic data.[11−13]
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