Roseoflavin, a Natural Riboflavin Analogue, Possesses In Vitro and In Vivo Antiplasmodial Activity

Abstract

The ability of the human malaria parasite Plasmodium falciparum to access and utilize vital nutrients is critical to its growth and proliferation. Molecules that interfere with these processes could potentially serve as antimalarials.

Mutation of theP. falciparumflavokinase confers resistance to roseoflavin and 8-aminoriboflavin

“…To investigate whether the RoF resistant parasites were cross-resistant to 8AF, we determined the sensitivity of the resistant parasites to 8AF. As the solubility of 8AF only permits testing up to 50 µM, we assessed the sensitivity in riboflavin-free RPMI where the IC 50 against WT parasites is 2 ± 0.4 nM rather than complete RPMI where the IC 50 of 8AF is 7 ± 1 µM 16 . The IC 50 values of 8AF in riboflavin-free medium against the RoF-A-E8, RoF-A-B6, RoF-B-E11, RoF-B-G2 parasite lines (1.2 ± 0.1 µM, 1.1 ± 0.1 µM, 1.2 ± 0.1 µM, 1.1 ± 0.1 µM, respectively) were found to be 1000-fold higher than those of the parent strain (0.0010 ± 0.0002 µM, P<0.0001, unpaired t-test; Figure 2B ).…”

“…Although we have recently shown that the parasite is capable of FMN and FAD synthesis 16 , the putative P. falciparum flavokinase gene remained to be experimentally verified and characterised. In this study, present data consistent with the putative Pf FK gene coding for a monofunctional flavokinase that utilises riboflavin, RoF and 8AF as substrates.…”

“…The antiplasmodial activity assays were performed in 96-well plates using the Malstat or SYBR-safe assay, as previously described [19][20][21] , with minor modifications 16 . At the end of the compound incubation period, plates were stored at -20 ºC for at least 24 hours prior to processing using SYBR-safe lysis or Malstat solutions.…”

“…We have recently shown that two analogues of riboflavin, namely roseoflavin (RoF, Figure 1 ) and 8-aminoriboflavin (8AF, Figure 1 ), inhibit the in vitro proliferation of P. falciparum by interfering with the utilisation of riboflavin 16 . We also found that RoF and 8AF reduce FMN and/or FAD levels within P. falciparum parasites, consistent with RoF and 8AF interacting with riboflavin metabolism enzymes, either as substrates or inhibitors 16 . However, the exact mechanism of action of these compounds is unknown.…”

Can we microbe-manage our vitamin acquisition for better health?

“…Due to these promising aspects, researchers have investigated these pathways to inhibit microbes. Recently, roseoflavin, a riboflavin analogue, was found to inhibit the proliferation of the malaria parasite [ 50 ]. Also, riboflavin synthase was selected as a therapeutic target to inhibit gut microbes involved in the development of colorectal cancer [ 51 ].…”