Antibiotics in Malaria Therapy and their Effect on the Parasite Apicoplast

Abstract

The impact of selected antibiotics on combating malaria infections was discovered in the mid of last century. Only recently, studies on their modes of action in malaria parasites have been initiated, prompted by the discovery of a prokaryotic organelle, the apicoplast. This plastid-derived structure, which originates from a secondary endosymbiotic event, possesses important metabolic as well as housekeeping functions, including fatty acid and heme biosynthesis. Due to its indispensability for parasite survival it represents a promising target for the use of antibiotics in malaria therapy. Most antibiotics cause a delayed death phenotype, which manifests in the late onset of antimalarial activity during the second replication cycle of the pathogen. This review will describe the effect of classical antibacterial agents against malaria parasites and the use of some of these compounds in clinical settings. Firstly we discuss the current knowledge about the physiological and morphological effects of antibiotics on the parasite and the apicoplast in particular, with special focus on the delayed death effect. Secondly antimalarial antibiotics are specified and their effects in vitro are compared with available in vivo data and clinical studies. Major precautions and side effects are described.

In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

“…It would be interesting to understand the mechanism for more prominent action of tigecycline against CQ-resistant strains and also potentiation of CQ action against resistant strains. Compared to earlier reports on delayed death of the malaria parasites with antibiotics [6, 20, 27], tigecycline seems to show faster anti-malarial action in vitro . However, in vitro activity of tetracycline observed in this activity was low compared to that reported earlier [27].…”

“…The spreading of resistance of P. falciparum to existing drugs, and recent reports on artemisinin resistance intensify the need for new anti-malarial agents [3–5]. Antibiotics with anti-malarial activity, in combination with traditional anti-malarial drugs, are potentially useful options for drug-resistant cases of malaria [6, 7]. Several antibiotics have shown promising anti-malarial effects and may be useful for malarial chemotherapy in combination with standard anti-malarial drugs [8, 9].…”

Chemical and genetic validation of thiamine utilization as an antimalarial drug target

“…In addition, given that both the apicoplast and the mitochondrion have been suggested to possess pathways that are viable antimalarial drug targets [39][40][41][42] , the demonstration here that a single drug is shown to interact with enzymes in both of these organelles, and inhibit at least one pathway that is essential to the intraerythrocytic development of the parasite, provides support for a multi-target antimalarial strategy using a single pharmacophore, potentially delaying the development of resistance. Our data also provide novel insights into possible redundancies between the mitochondrial and apicoplast biochemical pathways.…”

In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

“…It is intriguing, though, how subtle differences in structure resulted in the 10-fold difference in mean IC 50 values of BMS461996 and BMS411886. In a recent report, thiostrepton and its derivative have been shown to rapidly eliminate parasites by dually targeting the apicoplast protein synthesis and proteasome in the micromolar range (4,6,14,25). In comparison to thiostrepton, BMS461996 is water soluble and thus is biologically accessible for parasiticidal activity and results in irreversible growth inhibition within the first growth cycle, being therefore immediately effective.…”