Novel antibiotics for the treatment of gram-positive bacterial infections.
The natural dipeptide antibiotic TAN 1057 A,B displays excellent antibacterial activity against staphylococci including methicillin resistant Staphylococcus aureus. However, the in vitro activity against additional Gram-positive strains, in particular pneumococci and Enterococcus faecalis, proved to be considerably lower. We report the synthesis and pharmacological evaluation of new derivatives of this natural product that displayed increased antibacterial potency against staphylococci and were also active against pneumococci. In particular, the analogues bearing modified beta-homoarginine side chains with methylated guanidine moieties were shown to be significantly more potent than the natural product TAN 1057 A,B.
Brands
Michael
M
Business Group Pharma, Research, BAYER AG, Wuppertal D-42096, Germany.
Endermann
Rainer
R
Gahlmann
Reinhold
R
Krüger
Jochen
J
Raddatz
Siegfried
S
Stoltefuss
Jürgen
J
Belov
Vladimir N
VN
Nizamov
Shamil
S
Sokolov
Viktor V
VV
de Meijere
Armin
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018805:Sepsis / Q000401:mortality / Q000517:prevention & control; D013210:Staphylococcus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
C465773:5-(N-(3-amino-6-(1-methylguanidin-1-yl)hexanoyl)-N-methylamino)-5,6-dihydro-2-ureidopyrimid-4(1H)-one; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D006146:Guanidines; D011744:Pyrimidinones; C081415:TAN 1057A; C081416:TAN 1057B; D001120:Arginine