Segovia Xyonane, Srivastava Bhavya, Serrato-Arroyo Sergio, Guerrero Ashley, Huijben Silvie
The Center for Evolution and Medicine, School of Life Sciences, Arizona State University, Tempe, AZ, USA.
University of Zurich, Zurich, Switzerland.
Malar J. 2025 Mar 1;24(1):65. doi: 10.1186/s12936-025-05286-w.
Artemisinin-based combination therapy (ACT) remains a broadly effective anti-malarial drug combination, but the emergence of resistance is threatening its effectiveness. Limiting the spread of these drug-resistant parasites and delaying the emergence of resistance in new areas are of high priority. Understanding the evolution of resistance relies on discerning the fitness costs and benefits associated with resistance mutations. If the cost associated with resistance in an untreated host is sufficiently large relative to the benefit of resistance in a treated host, then the spread of resistance can be mitigated by ensuring sufficient hosts free from that active pharmaceutical ingredient. There is no straightforward way to measure these fitness costs, and each approach that has been used has its limitations. Here, the evidence of fitness costs as measured using field data, animal models, and in vitro models is reviewed for three of the main current or past first-line treatments for malaria: chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and artemisinin derivatives (ART). Despite the difficulties of assessing fitness costs, there is a good amount of evidence of fitness costs in drug-resistant Plasmodium falciparum parasites. The most persuasive evidence comes from resistance reversal observed following the cessation of the use of chloroquine. Comparable evidence cannot be obtained for SP- and ART-resistant parasites, due to the absence of complete cessation of these drugs in the field. Data from in vitro and animal models are variable. While fitness costs are often observed, their presence is not universal across all resistant strains. The extent and nature of these fitness costs can vary greatly depending on the specific genetic factors involved and the ecological context in which the parasites evolve. As a result, it is essential to avoid making broad generalizations about the prevalence or impact of fitness costs in drug-resistant malaria parasites. Focusing on fitness costs as a vulnerability in resistant parasites can guide their evolutionary trajectory towards minimizing their fitness. By accurately predicting these costs, efforts to extend the effectiveness of anti-malarials can be enhanced, limiting resistance evolution and advancing malaria control and elimination goals.
以青蒿素为基础的联合疗法（ACT）仍然是一种广泛有效的抗疟药物组合，但耐药性的出现正威胁着其有效性。限制这些耐药寄生虫的传播并延缓新地区耐药性的出现是当务之急。了解耐药性的演变依赖于识别与耐药突变相关的适应性成本和收益。如果未治疗宿主中与耐药性相关的成本相对于治疗宿主中耐药性的益处足够大，那么通过确保有足够多未接触该活性药物成分的宿主，就可以减缓耐药性的传播。没有直接的方法来衡量这些适应性成本，并且所使用的每种方法都有其局限性。在此，针对目前或过去三种主要的疟疾一线治疗药物：氯喹（CQ）、磺胺多辛-乙胺嘧啶（SP）和青蒿素衍生物（ART），综述了使用现场数据、动物模型和体外模型测量适应性成本的证据。尽管评估适应性成本存在困难，但有大量证据表明耐药恶性疟原虫存在适应性成本。最有说服力的证据来自氯喹停用后观察到的耐药性逆转。由于在现场没有完全停止使用SP和ART，因此无法获得针对SP和ART耐药寄生虫的类似证据。体外和动物模型的数据各不相同。虽然经常观察到适应性成本，但并非所有耐药菌株都普遍存在。这些适应性成本的程度和性质可能因所涉及的特定遗传因素以及寄生虫进化的生态环境而有很大差异。因此，必须避免对耐药疟原虫适应性成本的普遍性或影响进行广泛概括。将适应性成本视为耐药寄生虫的一个脆弱点，可以引导它们的进化轨迹朝着最小化其适应性的方向发展。通过准确预测这些成本，可以加强延长抗疟药物有效性的努力，限制耐药性进化并推进疟疾控制和消除目标。
