Anti-Candida activity of cispentacin: the active transport by amino acid permeases and possible mechanisms of action.
Cispentacin tranport into Candida albicans CCH442 was via a specific inducible proline permease and other amino acid permeases. Drug entry was also dependent upon the proton motive force. The apparent Km and Vmax for drug uptake under induced conditions were 0.4 mM and 7 nmol/microliter/min, respectively, with cellular accumulation in the mM range. Cispentacin uptake was competitively inhibited by L-proline with an apparent Ki of 75 microM. Cispentacin did not charge to transfer-RNA or incorporate into protein; however, the compound did inhibit in vivo incorporation of [14C]lysine into protein and [3H]adenine into RNA as well as in vitro [14C]proline charging to transfer-RNA. Cispentacin did not inhibit amino acid biosynthesis in vivo but did elevate levels of several amino acids possibly by interfering with self-regulatory mechanisms.
Capobianco
J O
JO
Anti-infective Research Division, Abbott Laboratories, Abbott Park, Il. 60064.
Zakula
D
D
Coen
M L
ML
Goldman
R C
RC
D026905:Amino Acid Transport Systems; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000935:Antifungal Agents; D001693:Biological Transport, Active; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism*; D012343:RNA, Transfer / Q000378:metabolism
D026905:Amino Acid Transport Systems; D000935:Antifungal Agents; D026901:Membrane Transport Proteins; D003515:Cycloleucine; C065594:cispentacin; D012343:RNA, Transfer; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase