Antimicrob Agents Chemother. 2010 Nov 22. [Epub ahead of print]
The antibiotic monensin causes cell cycle disruption of Toxoplasma gondii, mediated through the DNA repair enzyme TgMSH-1
Lavine MD, Arrizabalaga G.
Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Life Sciences South Room 142, Moscow, ID 83843, USA.
Monensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidian Toxoplasma gondii at an apparent late S-phase cell cycle checkpoint. In addition, experiments utilizing a monensin-resistant T. gondii mutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the Mut-S DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1 dependent cell cycle disruption is observed with the anti-parasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salynomicin on coccidial parasites, in which the drug activates a MSH-1 dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.
PMID: 21098240 [PubMed - as supplied by publisher]