**3. Drug resistance types: how much do we know in plasmodium?**

Drug resistance types include Intrinsic, acquired and adaptive resistance. Intrinsic drug resistance is a natural phenomenon, and an innate ability in pathogen for resisting drug or harmful substance without prior record of susceptibility [30, 31], pathogens do not necessarily develop mutation for this to occur [32]. Acquired drug resistance builds up in human host, and makes them unresponsive to a drug that should normally eliminate known pathogenic parasite from the host system [33], these are both stable forms of drug resistance. Adaptive resistance [34, 35] develops in a pathogen in response to stimuli [36].

While "intrinsic and acquired resistance are stable and can be transmitted vertically to subsequent generations "[32] adaptive resistance is temporal, unstable, and is often lost ([17]; [37]). [38] observed that "unstable adaptation contains modulation of gene expression, which results in phenotypic changes due to changes in environmental markers that are sensed by the microorganisms" but it is not certain how long this resistance is, or could be sustained [39]. Adaptive resistance is acquired through mutation and binding genetic plasticity that enables transfer of genes [20] from parasites to host. These different mode of drug resistance have been extensively studied and reported for bacteria [36, 40–42], but not much is seen in literature regarding adaptive resistance in plasmodium.

#### **4. Adaptive drug resistance has implications and consequences**

Development of drug resistance interferes with disease control, increase the cost of treatment and management of control programs and if not quickly address could thwart control programmes. The evolution of drug resistance in malaria parasites have been a focus of many research but there is a dearth of information regarding adaptive resistance in malaria parasite and the consequence in their human hosts. It is quite understandable since adaptive resistance only confers a temporal resistance

and is reversible. Although temporal and reversible, The possibility of mutation and evolution of a unique strain of parasite is possible, on which known drugs would be ineffective. However, the period between active activation of adaptive resistance in plasmodium, the product of activation (whether lethal or not, or novel and insensitive to known drugs or not), the consequence in gene transfer to host and a host of other factors are unknown.
