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Despite growing need to understand the mechanisms

Despite the immense interventions to reduce
mortality associated with malaria. The disease remains a global health problem
causing over 400,000 deaths per year (WHO, 2016). Given that the only available vaccine provides
less than 50% protection against clinical Plasmodium
falciparum infections (Olotu et al., 2013; The RTS, 2014), prevention and the treatment of malaria largely
rely on chemotherapy (use of drugs). The treatment of the uncomplicated P. falciparum malaria rests on the
artemisinin combination therapies (ACTs), which comprise of a short-acting
artemisinin derivative and a long-acting partner drug (WHO, 2016). The extensive use of the ACTs therapy is
correlated with the reduce mortality associated with malaria (WHO, 2016). Despite the extensive deployment of the ACTs in
which the partner drugs are predicted to act on different molecular targets of
the parasite, Plasmodium falciparum
has consistently evolved complex resistance mechanisms to all available
antimalarials including the artemisinin derivatives. The emergence of
artemisinin in South-East Asia, Cambodia, the epicentre of antimalarial drug
resistance (Miotto et al., 2015; Amato et al.,
2017; Imwong et al., 2017), demonstrates the growing need to understand the
mechanisms of action and resistance of the partner drugs.

The combination of artemether-lumefantrine (AL) is
the front-line ACT for treatment of P.
falciparum in many African countries including Kenya (Thu et al., 2017). The AL has proven to be highly effective against
widespread chloroquine (CQ) resistant parasite in most African countries (Mwai et al., 2012; Amambua-Ngwa et
al., 2017; Ayalew, 2017). In regions of high malaria endemicity, the
sustained effectiveness of the AL is primarily attributed to the long-acting LM
which acts on the residual parasites. However, not much attention has been
focused on understanding mechanisms of LM resistance despite the constant
selection pressure exposed to the drug. The
lumefantrine drug belongs to the class of the aryl alcohols and is structurally
related to mefloquine and quinine (Muller
and Hyde, 2010). Like the 4-aminoquinolines such as
chloroquine (CQ) and amodiaquine (AQ), LM is predicted to inhibit the
polymerization of the toxic heme in the digestive vacuole of the parasite, thus
killing the parasite using its own metabolic products (Warhurst,
Craig and Adagu, 2002; Combrinck et al.,
2013). However, LM is active against the CQ and AQ
resistant P. falciparum isolates ((Basco,
Bickii and Ringwald, 1998; Amambua-Ngwa et
al., 2017) meaning that the mechanisms of action and
resistance may be different. There is
a consensus that the Plasmodium
falciparum chloroquine resistance transporter
(Pfcrt) and the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) are the two key drug
transporters that modulate responses to both the aryl alcohols and the 4-aminoquinolines antimalarial drugs (Veiga et al., 2011, 2016). The alleles K76T
in Pfcrt and N86Y, Y184F, S1034C,
N1042D and D1246Y alleles in Pfmdr1
alter susceptibilities to quinoline and aryl alcohols antimalarial drugs. The P. falciparum isolates from Africa under
AL pressure selects the N86, 184F and D1246 alleles while the reciprocal
alleles are fixed by CQ, AQ or PQ pressure (Eyase et al., 2013; Taylor et al.,
2016; Amambua-Ngwa et al., 2017). It is, therefore, logical
to hypothesise that the primary mechanisms of action and resistance between CQ
and LM are different.

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The lack of well
characterised LM resistant P. falciparum
isolates has hindered comprehensive studies on the mechanisms of LM resistance.
Previous attempts to select LM
resistant P. falciparum line in vitro yielded unstable parasite line (Mwai et al., 2012). The transient drug-resistant phenotypes are
generally not amenable to map fixed resistance mutation but may reveal temporal harbinger molecular signatures associated with
the drug-resistant phenotypes. Using the unstable LM resistant
phenotypes, differentially expressed genes associated with the LM resistance in
P. falciparum were identified, for
instance, changes in expression of multidrug resistance gene 1 (pfmdr1), the multi-drug resistance
associated protein and the V-type H+ pumping pyrophosphatase 2 (pfvp2) were associated with LM
resistance (Mwai et al., 2012). Recently, the mutation (C591S) in the merozoite
surface protein Duffy binding-like 2 (MSPDBL2) was associated with LM
resistance in P. falciparum field
isolates from Kenyan individuals (Ochola-Oyier et al., 2015).


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