Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans

The study demonstrates the in vitro effectiveness of phenothiazine compound s, i.e. chlorpromazins and trifluoperazine against Candida albicans. Antica ndidal effect of these drugs is suggested to be because of their interactio n with Ca2+/calmodulin dependent protein phosphorylation. H-3-thymidine upt ake studies revealed that both these compounds affect the DNA synthesis alo ng with decrease in activities of nuclear calmodulin (CaM) and Ca2+/calmodu lin dependent protein kinase (CaMPK). Failure in cell growth was due to def ect in CaM mediated cell cycle arrest. Flow cytometric analysis showed that progression through GI and mitotic phase was affected when cells after cc- factor arrest were grown in the presence of chlorpromazine or trifluoperazi ne. These drugs also produced significant decline in the cellular lipids an d phospholipids. C-14-acetate incorporation studies further substantiated t hese results. We suggest that chlorpromazine or trifluoperazine affect the cell cycle through DNA synthesis (S phase) and cell division phases which a re governed by calmodulin and Ca2+/calmodulin dependent protein phosphoryla tion and lipids and phospholipids appear to be additional targets of phenot hiazine compounds in C. albicans. These results will have important signifi cance in the development of new anticandidal compounds. (C) 2001 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.