Abstract

Malaria remained a leading cause of morbidity and mortality in Sub-Saharan Africa, where Plasmodium falciparum 
demonstrates increasing resistance to multiple antimalarial agents. The molecular basis of this resistance involved 
complex genetic mutations affecting drug targets, transporters, and metabolic pathways, with significant 
implications for treatment efficacy across diverse African populations. This review aims to synthesized current 
understanding of antimalarial drug resistance mechanisms in Sub-Saharan Africa and evaluated their impact on 
clinical treatment outcomes, with emphasis on artemisinin-based combination therapies and partner drugs. A 
comprehensive analysis of peer-reviewed literature examining molecular resistance markers, biochemical 
mechanisms, pharmacogenetic factors, and clinical efficacy data from Sub-Saharan African populations was 
conducted. Resistance to chloroquine and sulfadoxine-pyrimethamine is widespread, mediated primarily by 
mutations in pfcrt, pfmdr1, pfdhfr, and pfdhps genes. Partial artemisinin resistance, characterized by kelch13 
mutations, remained rare but surveillance data indicated emerging concerns in East Africa. Partner drug resistance 
threatened artemisinin-based combination therapy effectiveness, with piperaquine and lumefantrine showing 
reduced efficacy in specific regions. Population-specific factors including cytochrome P450 polymorphisms, 
nutritional status, and transmission intensity modulated treatment responses. Molecular surveillance revealed 
geographic heterogeneity in resistance allele frequencies, correlating with variable treatment failure rated across 
the continent. Antimalarial drug resistance in Sub-Saharan Africa presented a multifaceted challenge requiring 
integrated molecular surveillance, individualized treatment approaches, and development of novel therapeutic 
strategies to maintain effective malaria control.