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Background <p>Sustained efficacy of artemisinin (ART)-based combination therapies is essential for controlling <i>Plasmodium falciparum</i> malaria in Africa. ART derivatives remain the key frontline treatment, while sulfadoxine-pyrimethamine is used for prevention. Recent detection in Africa of <i>P. falciparum kelch 13</i> (<i>k13</i>) substitutions associated with ART resistance (ART-R), distinct from Southeast Asian <i>k13</i> ART-R alleles, suggests local emergence. Together with widespread pyrimethamine resistance, ART-R poses a major public health concern. In the Democratic Republic of the Congo (DRC), however, data on resistance markers beyond conventional loci remain limited.</p> Methods <p>From June 2022 to February 2023, 303 malaria rapid diagnostic test-positive patients with uncomplicated malaria were enrolled at three clinics in Kinshasa, the Democratic Republic of the Congo (DRC). Day 1 parasitemia reduction rate (PRR) after artemether-lumefantrine treatment was assessed by microscopy. The gene region encoding the K13 propeller domain was sequenced from 171 microscopy-confirmed <i>P. falciparum</i> cases. Whole-genome sequencing data from 31 culture-adapted isolates were used to examine polymorphisms and copy number in 13 resistance-associated genes: <i>k13</i>, <i>coronin, kic4, kic5, kic7, px1</i>, <i>ap2-mu</i>, <i>ubp1</i>, <i>mdr1</i>, <i>mdr2</i>, <i>crt</i>, <i>dhfr</i>, and <i>dhps.</i></p> Results <p>No validated or candidate K13 propeller mutation associated with ART partial resistance was detected, including in samples from patients with &lt; 80% PRR. One isolate carried K13 A578S, a variant previously shown not to confer ART resistance. Whole-genome sequencing showed that all 13 genes were single copy and revealed diverse known and novel polymorphisms. K13 Asn-repeat variants and non-<i>k13</i> candidate variants, including PX1 M1701I/D1705N, AP2-Mu S160N, and UBP1 E1528D, were detected. Partner-drug and antifolate markers included MDR1 Y184F, the CRT chloroquine-resistant IET haplotype, the DHFR N51I/C59R/S108N triple-mutant haplotype, and DHPS K540E. Among variants compared between PRR groups, the synonymous <i>ap2-mu</i> a300c substitution remained significant after false discovery rate correction.</p> Conclusions <p>Established K13 propeller-mediated ART partial resistance was not evident in Kinshasa at the time of sampling. However, diverse non-<i>k13</i> candidate variants and persistent partner-drug and antifolate resistance markers support expanded molecular surveillance combined with clinical and ex vivo phenotypic monitoring.</p>

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Drug resistance gene polymorphisms of Plasmodium falciparum clinical isolates from Kinshasa, Democratic Republic of the Congo

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Mimie Bitshi,
  • Taeko K. Naruse,
  • Tomoyo Sakata-Kato,
  • Héritier Nzuau Mabi,
  • Prince Kassanda,
  • Gloria Kangite Yakenvu,
  • Evariste Tshibangu-Kabamba,
  • Papy Mandoko Nkoli,
  • Natsuko Kaku,
  • Yu Nakagama,
  • Yasutoshi Kido,
  • Dieudonné Mumba Ngoyi,
  • Osamu Kaneko

摘要

Background

Sustained efficacy of artemisinin (ART)-based combination therapies is essential for controlling Plasmodium falciparum malaria in Africa. ART derivatives remain the key frontline treatment, while sulfadoxine-pyrimethamine is used for prevention. Recent detection in Africa of P. falciparum kelch 13 (k13) substitutions associated with ART resistance (ART-R), distinct from Southeast Asian k13 ART-R alleles, suggests local emergence. Together with widespread pyrimethamine resistance, ART-R poses a major public health concern. In the Democratic Republic of the Congo (DRC), however, data on resistance markers beyond conventional loci remain limited.

Methods

From June 2022 to February 2023, 303 malaria rapid diagnostic test-positive patients with uncomplicated malaria were enrolled at three clinics in Kinshasa, the Democratic Republic of the Congo (DRC). Day 1 parasitemia reduction rate (PRR) after artemether-lumefantrine treatment was assessed by microscopy. The gene region encoding the K13 propeller domain was sequenced from 171 microscopy-confirmed P. falciparum cases. Whole-genome sequencing data from 31 culture-adapted isolates were used to examine polymorphisms and copy number in 13 resistance-associated genes: k13, coronin, kic4, kic5, kic7, px1, ap2-mu, ubp1, mdr1, mdr2, crt, dhfr, and dhps.

Results

No validated or candidate K13 propeller mutation associated with ART partial resistance was detected, including in samples from patients with < 80% PRR. One isolate carried K13 A578S, a variant previously shown not to confer ART resistance. Whole-genome sequencing showed that all 13 genes were single copy and revealed diverse known and novel polymorphisms. K13 Asn-repeat variants and non-k13 candidate variants, including PX1 M1701I/D1705N, AP2-Mu S160N, and UBP1 E1528D, were detected. Partner-drug and antifolate markers included MDR1 Y184F, the CRT chloroquine-resistant IET haplotype, the DHFR N51I/C59R/S108N triple-mutant haplotype, and DHPS K540E. Among variants compared between PRR groups, the synonymous ap2-mu a300c substitution remained significant after false discovery rate correction.

Conclusions

Established K13 propeller-mediated ART partial resistance was not evident in Kinshasa at the time of sampling. However, diverse non-k13 candidate variants and persistent partner-drug and antifolate resistance markers support expanded molecular surveillance combined with clinical and ex vivo phenotypic monitoring.