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  3. Acetyl-CoA synthetase mutations affect the susceptibility of Plasmodium falciparum to antimalarial drugs

Acetyl-CoA synthetase mutations affect the susceptibility of Plasmodium falciparum to antimalarial drugs

  • Microbiol Spectr. 2025 Oct 7;13(10):e0102625. doi: 10.1128/spectrum.01026-25.
Wei Zhao # 1 2,  Zheng Xiang # 1,  Weilin Zeng # 1,  Yucheng Qin 3,  Maohua Pan 3,  Yanrui Wu 1,  Mengxi Duan 1,  Ye Mou 1,  Tao Liang 1,  Yanmei Zhang 4,  Cheng Liu 1,  Xiuya Tang 1,  Yaming Huang 5,  Gongchao Yang 6,  Liwang Cui 7,  Zhaoqing Yang 1
Affiliations

Affiliations

  • 1 Yunnan Provincial Key Laboratory of Public Health and Biosafety & Department of Pathogen Biology and Immunology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan, China.
  • 2 Department of Clinical Laboratory, the Affiliated Hospital of Yunnan University, Kunming, Yunnan, China.
  • 3 Department of Infectious Diseases, Shanglin County People's Hospital, Chinese Center for Tropical Diseases Research Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Clinical Research Alliance for Parasitic Diseases Related Infectious Diseases, Nanning, Guangxi, China.
  • 4 Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
  • 5 Department of Protozoan Diseases, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China.
  • 6 Department of Advanced Biomedical Education, University of Mississippi Medical Center, Jackson, Mississippi, USA.
  • 7 Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
  • # Contributed equally.
PMID: 40932284 DOI: 10.1128/spectrum.01026-25
Abstract

Plasmodium falciparum Acetyl-CoA synthetase (PfAcAS) is an important source of acetyl-CoA. We detected mutations S868G and V950I in PfAcAS by whole-genome Sequencing analysis in certain recrudescent parasites after treatment with artesunate and dihydroartemisinin-piperaquine. Using CRISPR/Cas9 technology, we engineered Parasite lines to carry the PfAcAS S868G and V950I mutations in two genetic backgrounds and evaluated their susceptibilities to antimalarial drugs in vitro. The results demonstrated that PfAcAS S868G and V950I mutations alone or in combination affected the susceptibility of P. falciparum to several antimalarial drugs, including the artemisinin derivatives (dihydroartemisinin, artesunate, and artemether) and chloroquine, although absolute changes in susceptibilities were modest.IMPORTANCEMalaria, an infectious disease caused by Plasmodium parasites and transmitted by mosquitoes, continues to be one of the most pressing public health challenges worldwide. P. falciparum has demonstrated reduced sensitivity to artemisinin-based combination therapies (ACTs), thereby intensifying the difficulties associated with malaria management. Currently, only a limited number of molecular markers exist for identifying drug resistance in P. falciparum, and these markers do not fully elucidate the mechanisms behind this resistance. In this study, we performed whole-genome Sequencing analysis on P. falciparum strains that reemerged following ACT treatment. We aim to identify molecules potentially associated with drug resistance, which may provide new molecular markers for monitoring drug resistance in P. falciparum.

Keywords

Acetyl-CoA synthetase; Plasmodium falciparum; artemisinin; drug resistance.

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