**5. Drug resistance in** *P. falciparum*

Drug resistance is the reduction in the effectiveness of a medication such as an antimicrobial or an antineoplastic in curing a disease or condition [29]. The term is used in the context of pathogen that acquired survival potential in presence of drug. When an organism is resistant to more than one drug, it is said to be multidrug resistant.

*P. falciparum* resistance to chloroquine and sulphadoxine–pyrimethamine first developed on the in Southeast Asia and South America in the late 1950s and 1960s, respectively. The spread of resistant parasite strains elsewhere, including Africa, have been well documented retrospectively with molecular markers of the resistance to each drug. Chloroquine has been replaced by the combination of sulphadoxine and pyrimethamine (SP) in 1973. SP is widely used antimalarial worldwide and also used as the first line of treatment for malaria alone or in combination with other antimalarial drugs. SP resistance also became a big challenge to malaria control programs. For tackling this problem, SP was replaced by mefloquine but resistance to this new drug developed very rapidly. Mefloquine resistance was first observed in the late 1980s again in the same endemic area near the Thai-Cambodian border which spread out to Southeast Asia, South America and some pockets in Africa [30]. Resistance to SP was first described from the Thai-Cambodian border [31]. After chloroquine and sulphadoxine–pyrimethamine failures, Thailand introduced mefloquine in place of SP. For tackling this problem, Thailand imposed strict controls on its use but mefloquine resistance was first observed in the late 1980s and early 1990s again in the same endemic area near the Thai-Cambodian border. The increasing morbidity


*Recent Advances in Antimalarial Drug Discovery: Challenges and Opportunities DOI: http://dx.doi.org/10.5772/intechopen.97401*

> **Table 1.**

*Common antimalarial drugs and their mechanism of action.*

rate was reversed with the introduction of artemisinin. The introduction of the artemisinin saved millions of lives around the world [32]. Artemisinin leads to a high rate of recrudescence (reinfection of parasites) other drugs are required to clear the body of all parasites and prevent recurrence hence several more potent derivatives were synthesized *viz*., artesunate, arte-ether, arte-mether and dihydroartemisinin [33]. In 1995, Thailand replaced mefloquine with artesunate– mefloquine. The same combination was the first-line therapy in Cambodia from 2000 to 2012.

### **5.1 Resistance to artemisinin-based combination therapies**

To linger off artemisinin resistance, treatment for malaria is given as artemisinin based combination therapy (ACTs) in place of artemisinin alone or its derivative to treat uncomplicated malaria. ACT must include 1 artemisinin or its derivative another is other antimalarial drug or compound as prescribed by WHO 2001. ACTs are more efficient medicine today that is available, as it has great potential; it replaced antifolates and quinoline drug class which was used as the first-line treatment for *P. falciparum.*

Presently, artemisinin resistance is only prevalent in to the Cambodia, Thailand, Lao people's Democratic Republic [34], Viet Nam, Myanmar, and the Myanmar-China-India border area. In 2006, the declined efficacy of ASMQ (artesunate/mefloquine) was suspected for the first time on the Cambodia-Thailand border [35]. Thereafter, ASMQ clinical failures were reported on the Thailand-Myanmar border in correlation with delayed parasite clearance time [36]. Reason for resistance toward artemisinin derivatives because it promotes selection for partner-drug resistance mainly due to mismatches in the pharmacokinetics of the two drugs, causing frequent treatment failure of ACTs [37], amplification of pfmdr1 gene copy numbers. Clinical failures after dihydroartemisininpiperaquine (DHA/PPQ ) treatment have been reported, first in Cambodia in 2013 [38] and later in Vietnam in 2017 [39, 40] five and twelve years, respectively, after DHA/PPQ treatment introduction. DHA/PPQ resistance was confirmed by several reports and correlated with pfk13polymorphism, plasmepsin 2–3 gene amplification and single copies of the pfmdr1 gene [41]. Clinical failure rates greater than 10% have now been reported for the 5 ACTs in Cambodia, for 2 ACTs in Thailand and Lao PDR and for 1 ACT in Viet Nam, Myanmar, and in the Chinese and Indian border regions with Myanmar. It has been demonstrated that plasmepsin 2–3 gene amplification in DHA/PPQ resistant parasites is associated with pfmdr1 gene single copies, so these resistant parasites are sensitive to mefloquine [42]. In contrast, ASMQ-resistant parasites with pfmdr1 gene amplification are sensitive to piperaquine [37]. Based on the amplification of pfmdr1 gene copy numbers of ACT-resistant parasites, the alternating use of ASMQ and DHA/PPQ is under consideration.

#### **5.2 Potential chemotherapeutic target**

Developing resistance toward antimalarial drug has tinted requirement of new compound with antimalarial activity. To overcome this problem new validated drug target needed with detailed study of biochemical and metabolic processes of the parasite [43]. One way is to search for new drug(s) which inhibit parasite growth and cure malaria, secondly to find ways to reverse drug resistance mechanism. Research over the years have identified a number of potential drug targets mainly proteins in the parasite that can be utilized as drug targets.
