TY - JOUR
T1 - Di-alkylated paromomycin derivatives
T2 - Targeting the membranes of Gram positive pathogens that cause skin infections
AU - Berkov-Zrihen, Yifat
AU - Herzog, Ido M.
AU - Feldman, Mark
AU - Sonn-Segev, Adar
AU - Roichman, Yael
AU - Fridman, Micha
N1 - Funding Information:
This work was supported by the FP7-PEOPLE-2009-RG Marie Curie Action: Reintegration Grants (Grant 246673). We thank Professors Itzhak Ofek, Dani Cohen (Tel Aviv University), and Doron Steinberg (The Hebrew University of Jerusalem) for the gift of bacterial strains. We thank Anat Eldar-Boock from the group of Professor Ronit Satchi-Fainaro (Tel Aviv University) for her help with the hemolysis assays.
PY - 2013/6/15
Y1 - 2013/6/15
N2 - A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C7 and C8 linear aliphatic chains had improved antimicrobial activities relative to the parent aminoglycoside as well as to the clinically used membrane-targeting antibiotic gramicidin D; several novel derivatives were at least 16-fold more potent than the parent aminoglycoside paromomycin. Comparison between a di-alkylated and a mono-alkylated paromomycin indicated that the di-alkylation strategy leads to both an improvement in antimicrobial activity and to a dramatic reduction in undesired red blood cell hemolysis caused by many aminoglycoside-based cationic amphiphiles. Scanning electron microscopy provided evidence for cell surface damage by the reported di-alkylated paromomycins.
AB - A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C7 and C8 linear aliphatic chains had improved antimicrobial activities relative to the parent aminoglycoside as well as to the clinically used membrane-targeting antibiotic gramicidin D; several novel derivatives were at least 16-fold more potent than the parent aminoglycoside paromomycin. Comparison between a di-alkylated and a mono-alkylated paromomycin indicated that the di-alkylation strategy leads to both an improvement in antimicrobial activity and to a dramatic reduction in undesired red blood cell hemolysis caused by many aminoglycoside-based cationic amphiphiles. Scanning electron microscopy provided evidence for cell surface damage by the reported di-alkylated paromomycins.
KW - Amphiphilic aminoglycosides
KW - Cationic amphiphiles
KW - Hemolysis
KW - Membrane-targeting antibiotics
KW - Skin infection causing bacteria
UR - http://www.scopus.com/inward/record.url?scp=84878243608&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2013.03.046
DO - 10.1016/j.bmc.2013.03.046
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AN - SCOPUS:84878243608
SN - 0968-0896
VL - 21
SP - 3624
EP - 3631
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 12
ER -