Drug resistance of Plasmodium falciparum and Plasmodium vivax isolates in Indonesia

Abstract

This review article aims to investigate the genotypic profiles of Plasmodium falciparum and Plasmodium vivax isolates collected across a wide geographic region and their association with resistance to anti-malarial drugs used in Indonesia. A systematic review was conducted between 1991 and date. Search engines, such as PubMed, Science Direct, and Google Scholar, were used for articles published in English and Indonesian to search the literature. Of the 471 initially identified studies, 61 were selected for 4316 P. falciparum and 1950 P. vivax individual infections. The studies included 23 molecular studies and 38 therapeutic efficacy studies. K76T was the most common pfcrt mutation. K76N (2.1%) was associated with the haplotype CVMNN. By following dihydroartemisinin–piperaquine (DHA–PPQ) therapy, the mutant pfmdr1 alleles 86Y and 1034C were selected. Low prevalence of haplotype N86Y/Y184/D1246Ypfmdr1 reduces susceptibility to AS–AQ. SNP mutation pvmdr1 Y976F reached 96.1% in Papua and East Nusa Tenggara. Polymorphism analysis in the pfdhfr gene revealed 94/111 (84.7%) double mutants S108N/C59R or S108T/A16V in Central Java. The predominant pfdhfr haplotypes (based on alleles 16, 51, 59,108, 164) found in Indonesia were ANCNI, ANCSI, ANRNI, and ANRNL. Some isolates carried A437G (35.3%) or A437G/K540E SNPs (26.5%) in pfdhps. Two novel pfdhps mutant alleles, I588F/G and K540T, were associated with six pfdhps haplotypes. The highest prevalence of pvdhfr quadruple mutation (F57L/S58R/T61M/S117T) (61.8%) was detected in Papua. In pvdhps, the only polymorphism before and after 2008 was 383G mutation with 19% prevalence. There were no mutations in the pfk13 gene reported with validated and candidate or associated k13 mutation. An increased copy number of pfpm2, associated with piperaquine resistance, was found only in cases of reinfection. Meanwhile, mutation of pvk12 and pvpm4 I165V is unlikely associated with ART and PPQ drug resistance. DHA–PPQ is still effective in treating uncomplicated falciparum and vivax malaria. Serious consideration should be given to interrupt local malaria transmission and dynamic patterns of resistance to anti-malarial drugs to modify chemotherapeutic policy treatment strategies. The presence of several changes in pfk13 in the parasite population is of concern and highlights the importance of further evaluation of parasitic ART susceptibility in Indonesia. Graphical Abstract

Novel Benzotriazole‐β‐lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies

“…Table 1 shows the structure of synthesized compounds. First, 1H-benzo[d] [1,2,3]triazole (1) was converted into 2-(1H-benzo[d] [1,2,3]triazol-1-yl)acetic acid (3) by refluxing in the presence of 2-bromoacetic acid in aqueous sodium hydroxide. [50] Subsequent reaction of 2-(1Hbenzo[d] [1,2,3]triazol-1-yl)acetic acid (3) with Schiff base, tosyl chloride, and triethyl amine (Et 3 N) provided β-lactams 4a-j in moderate to good yields (Figure 2).…”

“…This suggests that the presence of naphthyl and anthracenyl substituents can be critical to the geometric orientation of compounds in the active site of the enzyme. The SAR study indicates that the β-lactam nitrogen moiety (R 1 ) plays a more significant role than the C-4 substituent R 2 , where R 2 is substituted phenyl ring. Comparison of β-lactam 4h bearing 4bromophenyl group at N-1 position, with an IC 50 of 14.40 μM, to the 4-iodo analog 4i (IC 50 of 25.65 μM) suggests that the size of the N-aryl group might be a factor.…”

“…There are about 100 countries around the world that still suffer from this infectious disease. [1,2] Malaria cases worldwide increased from 245 million in 2020 to 247 million in 2021, with most cases occurring in the WHO African region. [3] The infection is transmitted via the bite of Anopheles mosquitoes carrying Plasmodium parasites.…”

“…Plasmodium falciparum (P. falciparum) causes the most fatal form of human malaria, among different species of Plasmodium. [1,2] To control malaria effectively, scientists around the world are working on a variety of techniques, including medicines, insecticides, vaccinations, and bed nets sprayed with pesticides. [4][5][6][7] Even though medicines successfully treated malaria, resistance is a serious issue.…”

Large DNA fragment knock-in and sequential gene editing in Plasmodium falciparum: a preliminary study using suicide-rescue-based CRISPR/Cas9 system

“…Malaria remains a major global health burden and Plasmodium falciparum is the most lethal cause [ 1 ]. Spreading resistance to antimalarial drugs in the parasite and insecticides in the mosquito vectors [ 2 , 3 ], along with the lack of a broadly effective vaccine, is a challenge to sustain recent reductions in death and clinical disease and maintain a path toward malaria elimination. Unfortunately, progress toward developing new drugs and vaccines is slow, in large part due to our inadequate understanding of essential biological functions of P. falciparum and the large number of genes with unknown functions [ 4 ], even though it has been 20 years since the genome of P. falciparum was sequenced [ 5 ].…”