International Journal for Parasitology: Drugs and Drug Resistance最新文献_第4页

Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase 对硝基呋喃的机械、计算机和体外研究表明，它具有强大的利什曼尼杀灭活性和对锥虫硫酮还原酶的抑制作用

IF 3.4 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-08-01 DOI: 10.1016/j.ijpddr.2025.100605

Julia Andrés-Rodríguez , María-Cristina González-Montero , Nerea García-Fernández , Juan-José Galano-Frutos , Maria-Cristina de Rosa , Patricia Ferreira , María-Yolanda Pérez-Pertejo , Rosa M. Reguera , Rafael Balaña-Fouce , Carlos García-Estrada

Visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani is one of the neglected tropical diseases (NTDs) caused by trypanosomatids with treatment options limited to outdated drugs often causing adverse effects and promoting drug resistance. Previous antileishmanial drug discovery campaigns have identified nitroheterocyclic molecules with high efficacy and a high selectivity index. Therefore, we have evaluated on our screening platform of fluorescent L. donovani amastigotes, the antileishmanial activity of seven nitrofuran derivatives: furazolidone, nitrofurazone, nitrofurantoin, nifurtimox, 5-nitro-2-furaldehyde diacetate, PYZD-4409 and 5-nitro-2-furonitrile. These compounds showed good efficacy against axenic and intramacrophage amastigotes, most of them showing low cytotoxicity in mammalian cell lines. These nitrofuran derivatives induced reactive oxygen species production in axenic amastigotes and inhibited trypanothione reductase (TryR) either in uncompetitive or competitive manner, thus suggesting that their mechanism of action involves increased oxidative stress caused by an imbalance in redox metabolism. Furazolidone exhibited the most promising antileishmanial profile, and molecular docking analysis revealed consistency with the strongest TryR uncompetitive inhibitory effect, demonstrating its high affinity for an alternative binding site near the substrate (oxidized trypanothione) pocket. Docking results also highlighted PYZD-4409 as the compound with the highest binding affinity, and showed consistency with its competitive inhibition mechanism. Furthermore, similar binding modes identified across L. donovani TryR and other homologous proteins suggest the potential broad-spectrum activity of these nitrofuran derivatives, thus underscoring their importance as promising candidates for the development of novel antileishmanial therapies with broad-spectrum applications.

由婴儿利什曼原虫和多诺瓦利什曼原虫引起的内脏利什曼病是由锥虫虫引起的被忽视的热带病之一，治疗选择仅限于过时的药物，往往造成不良反应并促进耐药性。以往的抗利什曼原虫药物发现活动已经确定了具有高效和高选择性指数的硝基杂环分子。因此，我们在我们的荧光多诺瓦氏L. amastigotes筛选平台上，对呋喃酮、呋喃酮、呋喃妥英、呋喃替莫、5-硝基-2-呋喃醛二乙酸酯、PYZD-4409和5-硝基-2-呋喃腈7种呋喃衍生物的抗利什曼原虫活性进行了评价。这些化合物对无性系和巨噬细胞内无性系均有良好的抑制作用，多数在哺乳动物细胞系中表现出较低的细胞毒性。这些硝基呋喃衍生物诱导无源无尾线虫产生活性氧，并以非竞争或竞争的方式抑制锥体硫酮还原酶（TryR），从而表明它们的作用机制与氧化还原代谢失衡引起的氧化应激增加有关。呋喃唑酮显示出最有希望的抗利什曼原虫特征，分子对接分析显示其与最强的TryR非竞争性抑制效果一致，表明其对底物（氧化锥虫硫酮）口袋附近的替代结合位点具有高亲和力。对接结果也显示PYZD-4409是结合亲和力最高的化合物，与其竞争抑制机制一致。此外，在L. donovani TryR和其他同源蛋白中发现的类似结合模式表明，这些硝基呋喃衍生物具有潜在的广谱活性，因此强调了它们作为开发具有广谱应用的新型抗利什曼病治疗方法的有希望的候选物的重要性。

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引用次数: 0

Pharmacokinetics and metabolism of artemisinin (ART) in Plasmodium yoelii: ART-heme adduct as a potential biomarker for its resistance 青蒿素（ART）在约氏疟原虫体内的药代动力学和代谢：ART血红素加合物作为其耐药性的潜在生物标志物

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-07-12 DOI: 10.1016/j.ijpddr.2025.100603

Shanshan Du , Kun Xu , Zhaohua Liu , Jie Xing

Background

Plasmodium falciparum in Southeast Asia and Africa is developing resistance to the antimalarial drug artemisinin (ART). In this study, the metabolite of ART in P. yoelii parasites was evaluated as a potential biomarker for its antimalarial activity as well as its resistance.

Methods

The induced strain of P. yoelii (iPy) was first established after long-time pressure of ART in P. yoelii (Py)-infected mice. The metabolic and pharmacokinetic profiles of ART were then studied in both P. yoelii parasites and infected mice. The pharmacokinetic-pharmacodynamic behaviors of ART in two strains of P. yoelii (Py and iPy) were compared. The pharmacokinetic parameters (e.g., AUC and C_max) of ART metabolite in parasites were normalized by infected RBC (iRBC) burden.

Results

Lower antimalarial activity was found for ART against iPy than Py, in terms of the 90 % growth inhibitory dose (ED₉₀, 2.9-fold). In contrast with Py, mice infected with iPy could survive for at least 28 days. When ART was orally given to (i)Py-infected mice, ART was detected in parasites as ART-heme adduct. The plasma clearance of ART was not affected by (i)Py-infection, and higher plasma clearance of ART (by 3-4-fold) was found after multiple doses. After being normalized by iRBC, the exposure of ART-heme in P. yoelii parasites was dose-dependent, and its maximum concentration (C_max) was reached at 3–5 h. Compared with Py parasites, lower iRBC-normalized exposure of ART-heme (AUC_{0-t, normalized}) was found in iPy parasites (61.1 % of Py parasites) after an oral dose of ART to infected mice.

Conclusions

Plasma ART concentration merely reflected drug exposure in the host. ART-heme adduct was the major metabolite for ART in P. yoelii parasites, and it could be a potential biomarker for the antimalarial activity of ART as well as its resistance.

背景东南亚和非洲的恶性疟原虫正在对抗疟药物青蒿素（ART）产生耐药性。在本研究中，对ART在P. yoelii寄生虫中的代谢物进行了评估，作为其抗疟活性和耐药性的潜在生物标志物。方法在感染约氏疟原虫（Py）的小鼠体内，经长时间抗逆转录病毒（ART）压力，首次建立约氏疟原虫（iPy）诱导菌株。研究了ART在约尔氏疟原虫和感染小鼠体内的代谢和药代动力学特征。比较了ART在两株约氏疟原虫（Py和iPy）中的药动学-药效学行为。寄生虫体内ART代谢物的药代动力学参数（如AUC和Cmax）在感染红细胞（iRBC）负荷下归一化。结果以90%生长抑制剂量（ED90, 2.9倍）计算，ART对iPy的抗疟活性低于Py。与Py相比，感染iPy的小鼠至少可以存活28天。当口服ART给(i) py感染小鼠时，在寄生虫中检测到ART作为ART血红素加合物。(1) py感染不影响抗逆转录病毒的血浆清除率，多次给药后发现抗逆转录病毒的血浆清除率更高（3-4倍）。经iRBC归一化后，约氏疟原虫体内ART-血红素暴露量呈剂量依赖性，在3-5 h达到最大浓度（Cmax）。与Py寄生虫相比，经口服ART给药感染小鼠后，iPy寄生虫体内ART-血红素（AUC0-t，归一化）暴露量较Py寄生虫低（占Py寄生虫的61.1%）。结论血浆ART浓度仅反映宿主药物暴露情况。ART血红素加合物是约氏疟原虫中ART的主要代谢物，可作为ART抗疟活性和耐药性的潜在生物标志物。

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引用次数: 0

Antimalarial drug resistance and drug discovery: learning from the past to innovate the future 抗疟药耐药与药物发现：以史为鉴，创新未来

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-07-08 DOI: 10.1016/j.ijpddr.2025.100602

Liana Theodoridis, Teresa G. Carvalho

The emergence and spread of artemisinin-resistant malaria over the past 15 years has led to a recent rise in global malaria cases and represents a major public health concern. Following decades of intense research efforts, the first malaria vaccine has been approved for clinical use in October of 2021. However, its 36 % efficacy highlights the ongoing need for novel and effective drugs to combat malaria. The majority of current antimalarials are derivatives of previous efficient compounds whilst new treatments with diverse chemical scaffolds have not been implemented into clinical practice since 1996. We argue that current research efforts should focus on developing novel chemical classes of compounds to help fight drug resistant malaria. Here we provide a comprehensive review of the antimalarial treatments currently in clinical use and discuss their significant limitations due to parasite drug resistance. Further, we discuss various approaches to antimalarial drug discovery and offer new perspectives on the topic, informing on current methods, both rarely and extensively used. Collating the most recent and up-to-date drug discovery strategies will not only maximise current global research efforts but will ensure all possible drug development avenues are trialed. This review provides innovative insights to circumvent antimalarial drug resistance and diversify malaria therapeutics.

过去15年来，抗青蒿素疟疾的出现和传播导致全球疟疾病例最近有所增加，是一个重大的公共卫生问题。经过数十年的密集研究努力，首支疟疾疫苗于2021年10月获批用于临床。然而，其36%的效力突出表明，目前仍需要新的有效药物来防治疟疾。目前的大多数抗疟药是以前有效化合物的衍生物，而自1996年以来，使用各种化学支架的新疗法尚未在临床实践中实施。我们认为，目前的研究工作应该集中在开发新的化学类化合物上，以帮助对抗耐药疟疾。在这里，我们提供了一个全面的审查抗疟疾治疗目前在临床使用，并讨论其显著的局限性，由于寄生虫的耐药性。此外，我们讨论了抗疟疾药物发现的各种方法，并就该主题提供了新的观点，介绍了目前很少使用和广泛使用的方法。整理最新和最新的药物发现战略不仅将使当前的全球研究努力最大化，而且将确保所有可能的药物开发途径都得到试验。这一综述为规避抗疟药物耐药性和多样化疟疾治疗提供了创新见解。

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引用次数: 0

Type A asparagine synthetase in the zoonotic Cryptosporidium parvum (CpAsnA): Biochemical features and potential as a novel therapeutic target 人畜共患小隐孢子虫（CpAsnA）的A型天冬酰胺合成酶：生化特征及其作为新型治疗靶点的潜力

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-06-04 DOI: 10.1016/j.ijpddr.2025.100601

Zongzhen Zhai , Peng Jiang , Dongqiang Wang, Tao Chen, Jigang Yin, Guan Zhu

Cryptosporidium parvum is an intestinal protozoan parasite, the causative agent of the diarrheal cryptosporidiosis in humans and animals for which fully effective treatments are yet unavailable. The C. parvum genome encodes highly streamlined metabolic pathways, lacking enzymes to synthesize any amino acids de novo. However, it possesses a standalone type A asparagine synthetase (CpAsnA) that catalyzes the ammonia/ATP-dependent synthesis of asparagine from aspartate. Here, we expressed recombinant CpAsnA and characterized its enzyme functional parameters towards aspartate. We screened 5000 bioactive compounds using a thermal shift assay (TSA) and identified 31 hits showing high binding affinity to CpAsnA. Four of the 31 TSA hits exhibited lower micromolar activity against CpAsnA enzyme activity, including XD14, SB225002, histone acetyltransferase inhibitor II (HATi-II) and tolcapone. Among the four CpAsnA inhibitors, three displayed lower micromolar in vitro efficacy against the growth of C. parvum in vitro with satisfactory selectivity indices as primary antiparasitic hits. Our data suggest that CpAsnA merits further investigation as a potential drug target in the parasite.

小隐孢子虫是一种肠道原生动物寄生虫，是人类和动物腹泻隐孢子虫病的病原体，目前尚无完全有效的治疗方法。小孢子虫基因组编码高度流线型的代谢途径，缺乏酶来合成任何氨基酸。然而，它拥有一个独立的a型天冬酰胺合成酶（CpAsnA），催化氨/ atp依赖的天冬氨酸合成。在这里，我们表达了重组CpAsnA，并表征了其对天冬氨酸的酶功能参数。我们使用热移试验（TSA）筛选了5000种生物活性化合物，并确定了31个与CpAsnA具有高结合亲和力的命中点。31个TSA命中的4个对CpAsnA酶活性表现出较低的微摩尔活性，包括XD14、SB225002、组蛋白乙酰转移酶抑制剂II （hti -II）和tolcapone。在4种CpAsnA抑制剂中，有3种体外抑制小弧菌生长的微摩尔效应较低，选择性指标较好。我们的数据表明，CpAsnA作为寄生虫的潜在药物靶点值得进一步研究。

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引用次数: 0

Global equine parasite control guidelines: Consensus or confusion? 全球马寄生虫控制指南：共识还是困惑？

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-06-03 DOI: 10.1016/j.ijpddr.2025.100600

Martin K. Nielsen , Alison Pyatt , Jodie Perrett , Eva Tydén , Deborah van Doorn , Tina H. Pihl , Jennifer S. Schmidt , Georg von Samson-Himmelstjerna , Anne Beasley , Ghazanfar Abbas , Abdul Jabbar

Equine parasite control has historically been characterized by confusing and conflicting information, posing significant challenges for veterinarians and horse owners to make evidence-based decisions. Since 2012, equine parasite control guidelines have been developed and published for different parts of the world to address this situation and provide trusted sources of current guidance. At the 2024 International Equine Infectious Disease Conference in Deauville, Normandy, France, lead authors of equine parasite control guideline documents published in the USA, UK, Sweden, Denmark, the Netherlands, Australia, and Europe convened and presented their guidelines. This led to a discussion of differences and similarities between the guidelines and an effort to identify current research needs in this area. In general, all guidelines recommend a surveillance-based approach for equine parasite control, emphasizing the importance of anthelmintic resistance testing. Some guidelines have a focus on controlling Strongylus vulgaris, while others primarily focus on cyathostomins, ascarids and tapeworms. Although the same four anthelmintic drug classes are marketed in most countries, there are some differences between product portfolios available, most notably between Australia and other countries. European countries have various degrees of prescription-only restrictions on anthelmintic products, whereas products are available over the counter in Australia and the USA. Commercially available diagnostic portfolios differed somewhat between countries and affected recommendations made as well. In conclusion, the guidelines are in general agreement and are based on the same general principles. One major challenge is communicating the recommendations effectively to end-users, which should be made a priority going forward.

马寄生虫控制的历史特点是信息混乱和相互矛盾，这给兽医和马主做出基于证据的决定带来了重大挑战。自2012年以来，为世界不同地区制定和出版了马寄生虫控制指南，以应对这一情况，并提供可靠的现行指导来源。在法国诺曼底多维尔举行的2024年国际马传染病会议上，在美国、英国、瑞典、丹麦、荷兰、澳大利亚和欧洲发表的马寄生虫控制指南文件的主要作者召开会议并介绍了他们的指南。这导致了对指南之间的差异和相似之处的讨论，以及确定该领域当前研究需求的努力。总的来说，所有指南都建议采用基于监测的方法控制马寄生虫，强调进行驱虫耐药性检测的重要性。一些指导方针侧重于控制寻常圆形线虫，而另一些则主要侧重于cyathonstomins、蛔虫和绦虫。虽然在大多数国家都销售同样的四种驱虫药，但现有的产品组合之间存在一些差异，尤其是在澳大利亚和其他国家之间。欧洲国家对驱虫产品有不同程度的处方限制，而在澳大利亚和美国，产品可以在柜台购买。商业上可获得的诊断组合在各国之间有所不同，所提出的建议也受到影响。总之，这些指导方针大体上是一致的，并基于相同的一般原则。一项主要挑战是向最终用户有效地传达建议，这应成为今后的优先事项。

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引用次数: 0

Combination astragaloside IV and artesunate preserves blood–brain barrier integrity by modulating astrocytes and tight junction proteins in Plasmodium yoelii infection 黄芪甲苷联合青蒿琥酯通过调节约氏疟原虫感染中的星形细胞和紧密连接蛋白来保持血脑屏障的完整性

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-05-28 DOI: 10.1016/j.ijpddr.2025.100598

Phornyupa Sanguanwong , Ladawan Khowawisetsut , Lanaprai Kwathai , Peeraporn Varinthra , Chairat Turbpaiboon , Panapat Uawithya , Prasert Sobhon , Ingrid Y. Liu , Supin Chompoopong

Background

Astragaloside IV (ASIV), a natural compound from Astragalus membranaceus, exerts neuroprotective and anti-inflammatory effects in various pathologies. Its role in Plasmodium yoelii (Py) 17XL–induced inflammation leading to blood–brain barrier (BBB) damage remains undefined. Artesunate (ART), the frontline therapy for severe malaria, has encountered resistance and unresolved neurological sequelae. This study investigated the anti-inflammatory properties of ASIV combined with ART in Py-infected mice.

Methods

Sixty-five Institute of Cancer Research mice were randomized into 5 groups: sham, Py, Py-ART, Py-ASIV, and Py-ASIV + ART. Mice in Py groups were infected with Py 17XL. Either 25 mg/kg ASIV alone or 25 mg/kg ASIV plus 2.4 mg/kg ART was administered intraperitoneally for 5 days. Survival rate/time, parasitemia, neurological status, histopathology, and biochemical indices were evaluated.

Results

Although ASIV alone partially suppressed parasitemia, combination therapy significantly prolonged survival and mitigated neurological deficits. Both ASIV and ASIV + ART reduced IL-1β and TNF-α expression in serum and brain, attenuated BBB leakage (Evans blue assay), and preserved BBB integrity by decreasing astrocytic glial fibrillary acidic protein and aquaporin-4 while upregulating the tight junction proteins occludin and zonula occludens-1.

Conclusions

ASIV exhibited modest antiparasitic action and robust anti-inflammatory effects, alleviating BBB disruption when combined with ART in Py 17XL–infected mice. These findings provide an essential basis for further preclinical exploration of ASIV as an adjunct therapy in severe malaria.

黄芪甲苷（asigaloside IV， ASIV）是黄芪中的一种天然化合物，在多种疾病中具有神经保护和抗炎作用。它在约利疟原虫（Py） 17xl诱导的炎症导致血脑屏障（BBB）损伤中的作用尚不清楚。青蒿琥酯（ART）是治疗严重疟疾的一线药物，但遇到了耐药性和未解决的神经系统后遗症。本研究探讨了asv联合ART对pyy感染小鼠的抗炎作用。方法65只肿瘤研究所小鼠随机分为5组：sham组、Py组、Py-ART组、Py- asiv组和Py- asiv + ART组。Py组小鼠感染Py 17XL。单独25 mg/kg ASIV或25 mg/kg ASIV加2.4 mg/kg ART腹腔注射5天。评估生存率/时间、寄生虫血症、神经系统状况、组织病理学和生化指标。结果单抗部分抑制寄生虫血症，联合治疗可显著延长生存期，减轻神经功能缺损。asv和asv + ART均可降低血清和脑组织中IL-1β和TNF-α的表达，减少血脑屏障渗漏（Evans蓝试验），并通过降低星形胶质胶质纤维酸性蛋白和水通道蛋白-4，上调紧密连接蛋白occludin和occludens-1来保持血脑屏障的完整性。结论asiv在Py 17xl感染小鼠中表现出适度的抗寄生虫作用和强大的抗炎作用，与ART联合使用可减轻血脑屏障的破坏。这些发现为进一步探索ASIV作为重症疟疾辅助疗法的临床前研究提供了重要基础。

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引用次数: 0

New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans 对弯曲血蜱和秀丽隐杆线虫具有杀线虫活性的苯羟肟酸新衍生物

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-05-20 DOI: 10.1016/j.ijpddr.2025.100599

Josef Krátký , Markéta Zajíčková , Aya C. Taki , Oliver Michel , Petra Matoušková , Ivan Vokřál , Karolína Štěrbová , Ondřej Vosála , Beate Lungerich , Thomas Kurz , Robin B. Gasser , Karel Harant , Lenka Skálová

Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores the urgent need to discover and develop novel nematocidal drugs that target new molecular pathways. In the present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesized. Their anthelmintic activity was tested in the parasitic nematode Haemonchus contortus (barber's pole worm) and the free-living nematode Caenorhabditis elegans and potential toxicity assessed in mammalian models. Compound OMK211 showed the most promising results. It decreased viability and motility of larval and adult stages of both nematode species and of both drug-sensitive and drug-resistant strains of H. contortus at micromolar concentrations with the highest efficacy in H. contortus adult males (IC₅₀ ∼ 1 μM). Moreover, OMK211 was not toxic in mammalians cells in vitro and in mice in vivo. Consequently, thermal proteome profiling analysis was used to infer the putative molecular target of OMK211 in H. contortus. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184,900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting putative molecular target of new nematocidal drugs as its orthologs are present in several nematodes but not in mammals. In conclusion, novel derivatives of benzhydroxamic acid represent a promising new class of potential anthelmintics, which deserve further testing.

寄生线虫在包括人类在内的动物中引起广泛的疾病。然而，通常用于治疗这些感染的现有驱虫药的功效正在减弱，这是由于线虫种群中耐药性的日益普遍。这一日益严峻的挑战凸显了发现和开发针对新分子途径的新型杀线虫药物的迫切需要。本研究设计并合成了13种新型的苯羟肟酸衍生物。它们的驱虫活性在弯曲血线虫（巴氏杆虫）和秀丽隐杆线虫中进行了测试，并在哺乳动物模型中评估了潜在毒性。化合物OMK211的研究结果最为理想。微摩尔浓度可降低两种线虫幼虫和成虫阶段以及药敏菌株和耐药菌株的活力和运动能力，其中对成年雄性弯纹夜蛾的效果最高（IC50 ~ 1 μM）。此外，OMK211在体外和小鼠体内对哺乳动物细胞均无毒性。因此，热蛋白质组分析被用来推断出OMK211在H. tortortus中可能的分子靶点。结果显示，含有c2结构域的蛋白A0A6F7Q0A8是OMK211的相互作用伙伴，该蛋白由基因hcon_00184,900编码。利用先进的结构预测和对接工具，该蛋白被认为是新的杀线虫药物的一个有趣的假定分子靶点，因为它的同源物存在于几种线虫中，而不存在于哺乳动物中。综上所述，新型苯羟肟酸衍生物是一类有潜力的新型驱虫药，值得进一步研究。

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引用次数: 0

Resistance to apicoplast translational inhibitors in Plasmodium 疟原虫对顶质体翻译抑制剂的耐药性

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-05-10 DOI: 10.1016/j.ijpddr.2025.100597

Jessica L. Home, Geoffrey I. McFadden, Christopher D. Goodman

The spread of drug-resistant Plasmodium threatens malaria control efforts. Thus, understanding the mechanisms of resistance is crucial for implementing effective treatments and prevention strategies. The prokaryote-like translational machinery encoded by the apicoplast is the apparent target of several antibiotics with antimalarial activity. Among them, doxycycline and clindamycin are widely used for malaria treatment and/or chemoprophylaxis. However, the mechanisms underlying Plasmodium resistance to apicoplast-targeting antibiotics, and the evolution of such resistance mechanisms, remain largely unknown. In this review, we summarise reported cases of resistance to apicoplast translational inhibitors uncovered in either laboratory or clinical settings. We highlight the potential evolutionary pathway of doxycycline resistance, explore why resistance to these antibiotics remains rare in the field, and assess whether expanding their use in malaria treatment and prevention is a viable strategy.

耐药疟原虫的传播威胁着疟疾控制工作。因此，了解耐药机制对于实施有效的治疗和预防策略至关重要。由顶质体编码的原核样翻译机制是几种具有抗疟疾活性的抗生素的明显靶点。其中，强力霉素和克林霉素被广泛用于疟疾治疗和/或化学预防。然而，疟原虫对顶质体靶向抗生素耐药的机制以及这种耐药机制的演变在很大程度上仍然未知。在这篇综述中，我们总结了在实验室或临床环境中发现的对顶质体翻译抑制剂耐药的病例。我们强调了强力霉素耐药性的潜在进化途径，探讨了为什么对这些抗生素的耐药性在该领域仍然罕见，并评估了扩大它们在疟疾治疗和预防中的使用是否是一种可行的策略。

引用次数: 0

gdSir2.1 and gdSir2.3 are involved in albendazole resistance in Giardia duodenalis via regulation of the oxidative stress response gdSir2.1和gdSir2.3通过调控氧化应激反应参与十二指肠贾第虫对阿苯达唑的耐药性

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-05-05 DOI: 10.1016/j.ijpddr.2025.100596

Adrián Chávez-Cano , Scott C. Dawson , M. Guadalupe Ortega-Pierres

Albendazole resistance in Giardia duodenalis includes a complex and multifactorial challenge that potentially involves non-reported pathways such as the participation of metabolic regulators. In this context, sirtuins, known as metabolic sensors in various cellular processes, have emerged as promising candidates for novel anti-parasitic treatments. To investigate their role in albendazole (ABZ) resistance, initially we analyzed the expression of sirtuins in three Giardia strains resistant to 8 μM, 1.5 μM and 250 μM of ABZ that were obtained in our laboratory. Additionally, we used a CRISPRi-based knockdownstrategy to repress several sirtuins in Giardia and analyzed the effect of sirtuins on ABZ resistance. Our findings demonstrated a significant upregulation of sirtuins gdSir2.1, gdSir2.2 and gdSir2.3 in the three distinct albendazole-resistant lines. Knockdown of gdSir2.1 and gdSir2.3 resulted in heightened parasite susceptibility to both albendazole and hydrogen peroxide. Further, our study suggested that sirtuins contribute to the regulation of reactive oxygen species (ROS) levels, oxidative DNA damage, and the expression of oxidative stress response (OSR) genes within the parasite. Collectively, our results demonstrated that gdSir2.1 and gdSir2.3 play a significant role in mediating albendazole resistance, primarily through regulating the oxidative stress response.

十二指肠贾第虫对阿苯达唑的耐药性包括一个复杂的多因素挑战，可能涉及未报道的途径，如代谢调节因子的参与。在这种情况下，sirtuins，在各种细胞过程中被称为代谢传感器，已经成为新型抗寄生虫治疗的有希望的候选者。为了探讨sirtuins在阿苯达唑（ABZ）耐药性中的作用，我们首先分析了实验室获得的3株对阿苯达唑（ABZ） 8 μM、1.5 μM和250 μM耐药的贾第鞭虫菌株sirtuins的表达情况。此外，我们使用基于crispr的敲低策略来抑制贾第鞭虫中的几种sirtuins，并分析了sirtuins对ABZ耐药性的影响。我们的研究结果表明，在三种不同的阿苯达唑耐药品系中，sirtuins gdSir2.1、gdSir2.2和gdSir2.3显著上调。gdSir2.1和gdSir2.3的敲低导致寄生虫对阿苯达唑和过氧化氢的敏感性升高。此外，我们的研究表明sirtuins有助于调节寄生虫体内的活性氧（ROS）水平、氧化DNA损伤和氧化应激反应（OSR）基因的表达。总之，我们的研究结果表明，gdSir2.1和gdSir2.3主要通过调节氧化应激反应在介导阿苯达唑抗性中发挥重要作用。

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引用次数: 0

Three Asparagine insertions in the K13-propeller led to Plasmodium falciparum becoming resistant to multiple antimalarial drugs 在k13推进器中插入三个天冬酰胺导致恶性疟原虫对多种抗疟疾药物产生耐药性

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance

Pub Date : 2025-04-25 DOI: 10.1016/j.ijpddr.2025.100590

Zheng Xiang , Mengxi Duan , Siqi Wang , Hui Zhao , Wei Zhao , Xiaosong Li , Xinxin Li , Weilin Zeng , Yanrui Wu , Fuxue Yang , Xinyu Liu , Cong Tang , Liwang Cui , Zhaoqing Yang

Drug resistance in Plasmodium falciparum represents a significant challenge in malaria treatment. Identifying the molecular markers associated with P. falciparum resistance will effectively detect resistance and enhance treatment efficiency. In this study, we utilized the advanced CRISPR/Cas9 technology to precisely insert one, two, or three asparagine residues into the Kelch 13(K13) gene of the 3D7 strain, positioned after the 142nd amino acid residue, resulting in 1N-3D7, 2N-3D7, and 3N-3D7. Using ring-stage survival assays (RSA), drug sensitivity evaluations, and in vitro developmental assessments, our findings revealed a trend: 1) the insertion of asparagine residues into the parasite genome increased RSA, with more asparagine insertions leading to higher RSA. 2) According to the IC50 values, 1N-3D7 and 2N-3D7 exhibited similar sensitivity profiles across all ten tested drugs, with both demonstrating resistance to Naphthoquine, indicating that the insertions of one or two asparagines played an equivalent role in conferring resistance. However, the insertion of three asparagine residues resulted in significantly higher IC50 values compared to the first two forms when tested with Artesunate, Artemether, Dihydroartemisinin, Pyronaridine Phosphate, and Naphthoquine, showing resistance to all five drugs. Furthermore, 3N-3D7 exhibited a prolonged ring phase and a shortened trophozoite phase within red blood cells; the schizont phase appeared synchronous with the others, yet its mature schizonts contained fewer merozoites. Additionally, 3N-3D7 exhibited a fitness defect, with the proportion decreasing gradually during co-culture with 3D7, its fitness cost calculated as 14.88 ± 2.87. All these results support the opinion that the insertion of three asparagines was a molecular marker of resistance to artemisinin derivatives, Pyronaridine Phosphate, and Naphthoquine in P. falciparum.

恶性疟原虫的耐药性是疟疾治疗的一个重大挑战。鉴定恶性疟原虫耐药相关分子标记，将有效发现耐药性，提高治疗效率。在本研究中，我们利用先进的CRISPR/Cas9技术，在3D7菌株的Kelch 13（K13）基因中精确插入1、2或3个天冬酰胺残基，定位在第142个氨基酸残基之后，得到1N-3D7、2N-3D7和3N-3D7。通过环期生存试验（RSA）、药物敏感性评估和体外发育评估，我们的研究结果揭示了一个趋势：1)天冬酰胺残基插入寄生虫基因组增加了RSA，天冬酰胺插入越多，RSA越高。2)根据IC50值，1N-3D7和2N-3D7对10种被试药物的敏感性相似，均对萘醌产生耐药性，表明一种或两种天冬酰胺的插入对萘醌产生耐药性的作用相同。然而，当与青蒿琥酯、蒿甲醚、双氢青蒿素、磷酸吡啶和萘喹进行测试时，插入三种天冬酰胺残留物的IC50值明显高于前两种形式，显示出对所有五种药物的耐药性。3N-3D7红细胞内环期延长，滋养体期缩短；分裂体阶段与其他阶段同步，但其成熟分裂体含有较少的分裂子。3N-3D7存在适合度缺陷，在与3D7共培养过程中比例逐渐降低，其适合度成本计算为14.88±2.87。这些结果支持了3个天冬酰胺的插入是恶性疟原虫对青蒿素衍生物、磷酸吡啶和萘喹耐药的分子标记。

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引用次数: 0