Artemisinin-Resistant Plasmodium falciparum Malaria

Abstract

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins – the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs) – the first-line treatments for malaria – are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in-vitro, genomics, and transcriptomics studies in SEA have defined in-vivo and in-vitro phenotypes of artemisinin resistance; identified its causal genetic determinant; explored its molecular mechanism; and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's ‘K13’ gene; is associated with an upregulated “unfolded protein response” pathway that may antagonize the pro-oxidant activity of artemisinins; and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent; test whether new combinations of currently-available drugs cure ACT failures; and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to Sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

Toward a Metagenomic Understanding on the Bacterial Composition and Resistome in Hong Kong Banknotes

“…Bacteria with antibiotic resistance including methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) have been observed around the world (Bassetti et al, 2009; Raviglione and Sulis, 2016). Moreover, drug resistance in parasites/viruses such as malaria, HIV, and influenza has been also reported (Richman et al, 1994; Fairhurst and Dondorp, 2016; Li J. et al, 2016). The emergence of these resistant microorganisms has been accelerated by overusing of antibiotics on both humans (Llor and Bjerrum, 2014) and livestock (Landers et al, 2012).…”

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

“…More recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13, Pf3D7_1343700) were found to be highly prevalent in parasite populations of Cambodia and other Southeast Asian countries (9,12). In SEA, K13 propeller polymorphism is considered a reliable molecular marker of ART-resistant P. falciparum parasites, which show increased survival rates in RSAs and delayed clearance (i.e., "D3 positivity") in ACT-treated patients (13). Although D3 positivity is considered a useful tool to detect the emergence of ART resistance in a population (14), especially in resource-limited countries where standardized parasite clearance studies (15) are not feasible, the results can be confounded by host immunity and initial parasite density (14); therefore, follow-up studies to obtain parasite clearance half-life data are needed to confirm D3-positivity rates.…”

Oxidative stress in malaria and artemisinin combination therapy: Pros and Cons

“…K‐13 polymorphisms C580Y, R539T, Y493H, M476I, and I543T were associated with artemisinin resistance in laboratory parasite lines and subsequently proven in field isolates . Such mutations and several others were as well found in more than 18 countries in sub‐Saharan Africa though in low frequencies (reviewed in ). The discovery of k‐13 was the first evidence for artemisinin resistance.…”