Dahl Erica L, Rosenthal Philip J
Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0811, USA.
Antimicrob Agents Chemother. 2007 Oct;51(10):3485-90. doi: 10.1128/AAC.00527-07. Epub 2007 Aug 13.
Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.
几类抗生素具有抗疟活性。抗生素抗疟原虫的作用机制尚不清楚，先前的研究结果相互矛盾，部分原因是这些研究使用的是超药理浓度的抗生素。我们研究了阿奇霉素、环丙沙星、克林霉素、强力霉素和利福平对氯喹耐药（W2）和氯喹敏感（3D7）恶性疟原虫菌株的抗疟作用。在临床相关浓度下，利福平能迅速杀死疟原虫，阻止其开始细胞分裂。相比之下，阿奇霉素、环丙沙星、克林霉素和强力霉素的药理浓度最初对疟原虫相对无活性，但会产生延迟死亡效应，即经处理的疟原虫后代无法完成红细胞内发育。导致延迟死亡的药物不会改变顶质体向发育后代的分布。然而，经处理的疟原虫后代继承的顶质体是异常的。随着抗生素处理的疟原虫后代开始细胞分裂，顶质体功能丧失变得明显，裂殖体无法完全成熟或红细胞无法破裂。这些发现解释了多种抗生素抗疟作用缓慢的原因。
