Structure-activity relationship of glycine betaine analogs on osmotolerance of enteric bacteria.
Bacterial cells have the ability to accumulate compatible solutes within the cytoplasm to maintain their osmolarity above that of the extracellular milieu. Glycine betaine (GB) and its biosynthetic precursor choline (Chol) are the major compatible solutes that bacteria accumulate when osmotically challenged. Different osmotically triggered active transport mechanisms have been identified for GB and Chol. In the present study we examined the bioisosteric replacement of the carboxylic group of GB with sulfonic, phosphonic or benzenesulfonamido groups. The sulfonic acid analog (sulfobetaine, compound 3) showed osmoprotectant activity equivalent to that of GB. In addition, we tested the possibility of utilizing GB/Chol transport systems to deliver cytotoxic analogs of GB into three strains of E. coli that differed in their salt resistance. We found that N1-betainyl-N4-(haloacetyl)sulfanilamides (compounds 17c-e) that are GB analogs containing alkylating side chain within their structures inhibited the bacterial growth of the tested standard and salt sensitive strains of E. coli. We also showed that the (N-methyl-cyclic ammonio)methanesulfonates (compounds 21a-c) are able to block Chol transport system in both the standard and the salt-sensitive E. coli strains used. At the concentration used (0.1 mM), none of the tested compounds showed any significant effect on the salt-resistant strain used.
Abdel-Ghany
Y S
YS
Department of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus 43210.
Ihnat
M A
MA
Miller
D D
DD
Kunin
C M
CM
Tong
H H
HH
D001622:Betaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D001693:Biological Transport, Active / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D009994:Osmolar Concentration; D013329:Structure-Activity Relationship
D001622:Betaine