Abstract:
: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 MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an 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.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Lavine MD,Arrizabalaga Gdoi
10.1128/AAC.01092-10subject
Has Abstractpub_date
2011-02-01 00:00:00pages
745-55issue
2eissn
0066-4804issn
1098-6596pii
AAC.01092-10journal_volume
55pub_type
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