In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

Abstract

b Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC 50 s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC 50 s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC 50 , gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation.

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…498 Thus, unlike other eukaryotes, P. falciparum is sensitive to many thiopeptides such as thiostrepton, micrococcin, and GE2270, and nocathiacin. 499–508 Other protein synthesis inhibitors also have demonstrated a similar anti-malarial activity. 509–511 However, it should be noted that protease inhibitors are additionally known to be active against the Plasmodium parasite, as the proteasome is crucial for development.…”

Tetracyclines in malaria

“…Their mechanisms of action on Plasmodium have not been as well described, although a number of studies have addressed this issue. There are three categories of ribosomes in Plasmodium : mitochondrial, plastid and nuclear [ 28 ]. As suggested by three studies [ 29 – 31 ], tetracycline may directly inhibit mitochondrial protein synthesis and also decrease the activity of a mitochondrial enzyme (i.e., dihydroorotate dehydrogenase) involved in de novo pyrimidine synthesis [ 32 ].…”

“…Doxycycline at a dose of 100 mg/day starting at the day of arrival in endemic areas and continuing for up to 4 weeks after returning, still remains highly effective as P. falciparum prophylaxis. Concerning the treatment of malaria, studies conducted in the 1950s [ 28 , 39 ] and in 1970 [ 40 , 41 , 66 , 67 ] have shown the effectiveness of cycline monotherapy in treating simple access to P. falciparum . Later, the need for a minimum 7-day treatment was demonstrated; the disappearance of parasites was effective only after 5 days at a dose of 200 mg daily [ 68 ].…”

Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?

“…A water-soluble derivative of nocathiacin exerted an irreversible growth inhibition within the first growth cycle at a nanomolar range against chloroquine-susceptible and resistant P. falciparum strains and was immediately effective [120]. Further investigations need to be done on this drug and its derivatives to understand its mode of action P. falciparum .…”