Drug Resistance Updates最新文献

英文中文

RNF26 regulating Tumor Immunogenicity of Hepatocellular carcinoma by Degrading GRP78 and Instigating ER Stress RNF26通过降解GRP78和促进内质网应激调节肝癌的肿瘤免疫原性

IF 24.3 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-02-08 DOI: 10.1016/j.drup.2026.101375

Jiajing Luo, Han Zhuo, Minghui Zheng, Yi Fang, Xuran Wang, Yangyang Jin, Yaoyao Li, Siyu Du, Jie Wang, Cailin Xue, Runqiu Jiang, Gang Li

引用次数: 0

Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation SPI1的棕榈酰化修饰通过抑制c- cbll介导的泛素化和降解促进鼻咽癌的放射耐药

IF 24.3 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-02-05 DOI: 10.1016/j.drup.2026.101374

Li Jiang, Ying Bin, Yaoyi Huang, Lanhua Wu, Xingyue Qiu, Youchang Du, Jinglin Mi, Kang Liu, Yayan Deng, Jiancheng Ning, Mingxuan Li, Zhen Meng, Yating Qin, Huisi Zhang, Tianyu Wu, Ding Liang, Zuoting Cao, Min Kang

引用次数: 0

A novel frameshift mutation in a case of therapy-resistant metastatic pheochromocytoma 一个新的移码突变在治疗耐药转移性嗜铬细胞瘤的情况下

IF 24.3 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-02-04 DOI: 10.1016/j.drup.2026.101373

Xiao-yu Jing, Guo-qian He, Xia Guo

引用次数: 0

Cellular senescence in cancer: Friend or fraud? 癌症中的细胞衰老：是朋友还是骗子？

IF 24.3 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-31 DOI: 10.1016/j.drup.2026.101363

Qingxin Chen, Jianxin Liu, Jianming Wu, Xin Xiang, Xiaogang Zhou, Jianing Mi, Jing Wei, Xiao Zou, Anguo Wu

引用次数: 0

Host-directed novel mechanistic insights of doxorubicin reveal its efficacy against drug-resistant HSV-1 underscoring risks with oncolytic virotherapy 宿主导向的阿霉素新机制揭示其对耐药HSV-1的疗效，强调溶瘤病毒治疗的风险

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-29 DOI: 10.1016/j.drup.2026.101362

Pankaj Sharma , Divya Kapoor , Sudhanshu Kumar Singh , Xiang Shen , Chandrashekhar D. Patil , Deepak Shukla

Background

Herpes simplex virus type 1 (HSV-1) infects approximately four billion people worldwide, and the emergence of drug-resistant strains has reduced the effectiveness of existing antivirals. Targeting host pathways exploited by HSV-1 represents an attractive strategy for developing resistance-refractory antivirals.

Methods

We evaluated the antiviral potential of doxorubicin, an FDA-approved anticancer drug, against HSV-1 using in vitro cell culture systems, an ex vivo porcine corneal model, and an in vivo murine ocular infection model. Viral replication, host signaling pathways, and combinatorial interactions with nucleoside analogs were systematically assessed.

Results

Doxorubicin potently inhibited HSV-1 replication at sub-cytotoxic concentrations by suppressing the host PI3K-AKT-mTOR signaling axis, a pathway required for viral entry and productive replication. Antiviral activity was observed against laboratory-adapted strains as well as clinical acyclovir-resistant HSV-1 isolates. Pharmacological modulation of PI3K-AKT signaling, pathway activation kinetics, and studies in doxorubicin-resistant cells confirmed a host-directed mechanism. Doxorubicin exhibited strong synergy with nucleoside analog antivirals, enabling dose reduction without loss of efficacy. While inhibition of PI3K-AKT signaling constrained productive replication of both wild-type and oncolytic HSV-1, these effects were context-dependent and relevant to therapeutic settings that rely on robust viral replication.

Conclusions

This study identifies PI3K-AKT pathway inhibition as a novel host-directed antiviral mechanism underlying doxorubicin’s activity against HSV-1, demonstrates its synergistic potential with nucleoside analogs, and provides mechanistic insight into raising concerns over oncolytic HSV-based therapies. Collectively, these findings highlight the potential of localized, host-targeted strategies for managing drug-resistant HSV-1 infections.

背景1型单纯疱疹病毒（HSV-1）感染了全世界大约40亿人，耐药菌株的出现降低了现有抗病毒药物的有效性。靶向HSV-1利用的宿主途径是开发耐药抗病毒药物的一种有吸引力的策略。方法采用体外细胞培养系统、离体猪角膜模型和小鼠眼部感染模型，对fda批准的抗癌药物阿霉素对HSV-1的抗病毒潜力进行了评价。系统地评估了病毒复制、宿主信号通路以及与核苷类似物的组合相互作用。结果阿霉素通过抑制宿主PI3K-AKT-mTOR信号轴，在亚细胞毒浓度下有效抑制HSV-1的复制，PI3K-AKT-mTOR信号轴是病毒进入和高效复制所必需的途径。观察到对实验室适应株和临床无环韦耐药HSV-1分离株的抗病毒活性。PI3K-AKT信号的药理调节、通路激活动力学以及在阿霉素耐药细胞中的研究证实了其宿主导向的机制。阿霉素表现出与核苷类似抗病毒药物的强协同作用，使剂量减少而不丧失疗效。虽然PI3K-AKT信号的抑制抑制了野生型和溶瘤性HSV-1的有效复制，但这些影响是依赖于环境的，并且与依赖于稳健病毒复制的治疗环境相关。结论本研究确定了PI3K-AKT通路抑制是阿霉素抗HSV-1活性的一种新的宿主抗病毒机制，证明了其与核苷类似物的协同作用潜力，并为提高对溶瘤性hsv治疗的关注提供了机制见解。总的来说，这些发现突出了管理耐药HSV-1感染的局部、针对宿主的策略的潜力。

{"title":"Host-directed novel mechanistic insights of doxorubicin reveal its efficacy against drug-resistant HSV-1 underscoring risks with oncolytic virotherapy","authors":"Pankaj Sharma , Divya Kapoor , Sudhanshu Kumar Singh , Xiang Shen , Chandrashekhar D. Patil , Deepak Shukla","doi":"10.1016/j.drup.2026.101362","DOIUrl":"10.1016/j.drup.2026.101362","url":null,"abstract":"<div><h3>Background</h3><div>Herpes simplex virus type 1 (HSV-1) infects approximately four billion people worldwide, and the emergence of drug-resistant strains has reduced the effectiveness of existing antivirals. Targeting host pathways exploited by HSV-1 represents an attractive strategy for developing resistance-refractory antivirals.</div></div><div><h3>Methods</h3><div>We evaluated the antiviral potential of doxorubicin, an FDA-approved anticancer drug, against HSV-1 using <em>in vitro</em> cell culture systems, an <em>ex vivo</em> porcine corneal model, and an <em>in vivo</em> murine ocular infection model. Viral replication, host signaling pathways, and combinatorial interactions with nucleoside analogs were systematically assessed.</div></div><div><h3>Results</h3><div>Doxorubicin potently inhibited HSV-1 replication at sub-cytotoxic concentrations by suppressing the host PI3K-AKT-mTOR signaling axis, a pathway required for viral entry and productive replication. Antiviral activity was observed against laboratory-adapted strains as well as clinical acyclovir-resistant HSV-1 isolates. Pharmacological modulation of PI3K-AKT signaling, pathway activation kinetics, and studies in doxorubicin-resistant cells confirmed a host-directed mechanism. Doxorubicin exhibited strong synergy with nucleoside analog antivirals, enabling dose reduction without loss of efficacy. While inhibition of PI3K-AKT signaling constrained productive replication of both wild-type and oncolytic HSV-1, these effects were context-dependent and relevant to therapeutic settings that rely on robust viral replication.</div></div><div><h3>Conclusions</h3><div>This study identifies PI3K-AKT pathway inhibition as a novel host-directed antiviral mechanism underlying doxorubicin’s activity against HSV-1, demonstrates its synergistic potential with nucleoside analogs, and provides mechanistic insight into raising concerns over oncolytic HSV-based therapies. Collectively, these findings highlight the potential of localized, host-targeted strategies for managing drug-resistant HSV-1 infections.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101362"},"PeriodicalIF":21.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overcoming therapeutic resistance in oncology: The prospects of inorganic nanotheranostics 克服肿瘤治疗耐药：无机纳米治疗的前景

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-28 DOI: 10.1016/j.drup.2026.101361

Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng

Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.

癌症仍然是全球死亡的主要原因，治疗耐药性构成了巨大的临床障碍。无机纳米肿瘤学——集诊断和治疗能力于一体的多功能平台——为克服这一障碍提供了一个有希望的策略。本综述系统地研究了不同类别的无机纳米材料（包括铁、钆、钛、金、锰、碳和硅基系统）是如何通过独特的物理化学性质和生物相互作用来抵消特定的抗性机制的。我们强调了它们在增强药物传递，调节肿瘤微环境，实现精确成像以及与化疗，放疗和免疫治疗等各种治疗方式协同作用方面的作用。讨论了刺激反应设计、靶向递送和组合治疗的进展。最后，我们批判性地评估了转化挑战——包括药代动力学、长期安全性和生产可扩展性——并概述了肿瘤临床有效、个性化纳米治疗干预的未来方向。

{"title":"Overcoming therapeutic resistance in oncology: The prospects of inorganic nanotheranostics","authors":"Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng","doi":"10.1016/j.drup.2026.101361","DOIUrl":"10.1016/j.drup.2026.101361","url":null,"abstract":"<div><div>Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101361"},"PeriodicalIF":21.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor immune organoids in immunotherapy resistance and drug screening 肿瘤免疫类器官在免疫治疗中的耐药性和药物筛选

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-23 DOI: 10.1016/j.drup.2026.101360

Minghui Zhang , Lijun Li , Haihong Pu , Yan Wang , Xiaoxin Zhang , Xiaotian Guo , Yanbin Zhao , Qingwei Meng , Mingzhu Yin

Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.

肿瘤类器官是癌症研究中的一种变革性工具，因为它们保留了亲代肿瘤的遗传和表型特征，并准确地概括了它们的异质性。然而，肿瘤类器官的局限性之一在于肿瘤微环境（TME）中缺乏免疫细胞和基质细胞。为了应对这一挑战，肿瘤免疫类器官已经被开发出来，它包含复杂的免疫和间质室，而不仅仅是保存肿瘤结构。肿瘤免疫类器官在研究个体化免疫治疗反应和免疫治疗耐药机制方面具有很大的潜力。然而，将这些模型整合到临床实践中仍然具有挑战性。在这篇综述中，我们概述了目前可用的和快速发展的肿瘤免疫类器官，概述了TME和免疫治疗的效果。这些肿瘤免疫类器官可以通过传统的肿瘤类器官与基质细胞和免疫细胞共培养，以及利用微流体和气液界面（ALI）培养技术保存TME来建立。此外，我们描述了肿瘤免疫类器官在揭示肿瘤内在和外在免疫治疗耐药机制、预测免疫治疗疗效和促进新药筛选方面的应用。最后，我们强调了类器官培养技术目前面临的挑战，这些挑战需要在基础和转化癌症研究中得到更广泛的应用。本文综述为今后应用肿瘤免疫类器官研究免疫治疗耐药机制、开发个性化免疫治疗提供理论基础。随着技术的不断进步，肿瘤免疫类器官有望在癌症免疫治疗中发挥越来越重要的作用，为患者提供更有效、更有针对性的治疗选择。

{"title":"Tumor immune organoids in immunotherapy resistance and drug screening","authors":"Minghui Zhang , Lijun Li , Haihong Pu , Yan Wang , Xiaoxin Zhang , Xiaotian Guo , Yanbin Zhao , Qingwei Meng , Mingzhu Yin","doi":"10.1016/j.drup.2026.101360","DOIUrl":"10.1016/j.drup.2026.101360","url":null,"abstract":"<div><div>Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101360"},"PeriodicalIF":21.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acetylation-mediated fluconazole inactivation: A novel antifungal resistance mechanism 乙酰化介导的氟康唑失活：一种新的抗真菌抗性机制

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-23 DOI: 10.1016/j.drup.2026.101359

Ludmila Gouveia-Eufrasio , Gustavo José Cota de Freitas , Danielle Letícia da Silva , Iara Rinco Silva , Daniel Santana de Carvalho , Milton T. Drott , Bruna Carolina Teixeira Almeida , Cesar da Silva Santana Moura , Beatriz Murta Rezende Moraes Ribeiro , Maria Fernanda Liphaus Almeida Negreli , Lucas Cecilio Vilar , Silvia Maria Cordeiro Werneck , Grace Santos Tavares Avelar , Álan Natanael Pereira Gomes , Isabela Lima de Miranda , Mariana Guerra de Aguilar , Rossimiriam Pereira de Freitas , Luana Rossato , Rafael Wesley Bastos , Lívia Kmetzsch , Daniel Assis Santos

Antifungal resistance is considered a global health threat. However, enzymatic inactivation of antifungals, a common mechanism seen in antibacterial resistance, has not yet been described in fungi. From a One Health perspective, this study demonstrates that Cryptococcus deuterogattii and C. neoformans, the leading agents of cryptococcosis, enzymatically inactivate fluconazole. Agrochemicals induce the overexpression of genes that code for acetyltransferases, specifically GCN5 and NAT10. These enzymes catalyze the acetylation of fluconazole into O-acetyl-fluconazole. This metabolite is unable to properly bind to 14-α-demethylase, the azole target, abolishing the antifungal activity. GCN5 and NAT10 inhibitors constrained acetylation and restored fluconazole activity, highlighting their potential as therapeutic adjuvants. The same phenotype was observed in other fungal species, suggesting broader relevance. Furthermore, O-acetyl-fluconazole was also detected in cerebrospinal fluid from cryptococcal meningitis patients undergoing fluconazole treatment. These findings reveal a previously unrecognized antifungal resistance mechanism and suggest that environmental traits shape clinically relevant resistance through conserved enzymatic pathways.

抗真菌药物耐药性被认为是全球健康威胁。然而，抗真菌酶的失活是一种常见的抗细菌耐药性机制，但尚未在真菌中得到描述。从One Health的角度来看，本研究表明隐球菌病的主要病原体deuterogattii隐球菌和新生隐球菌可以酶灭氟康唑。农用化学品诱导编码乙酰转移酶的基因过度表达，特别是GCN5和NAT10。这些酶催化氟康唑的乙酰化成o -乙酰基氟康唑。该代谢物不能与14-α-去甲基化酶（唑的靶标）结合，从而取消了抗真菌活性。GCN5和NAT10抑制剂抑制乙酰化并恢复氟康唑活性，突出了它们作为治疗佐剂的潜力。在其他真菌物种中也观察到相同的表型，表明具有更广泛的相关性。此外，在接受氟康唑治疗的隐球菌性脑膜炎患者的脑脊液中也检测到o -乙酰-氟康唑。这些发现揭示了一种以前未被认识到的抗真菌耐药性机制，并表明环境特征通过保守的酶途径塑造了临床相关的耐药性。

{"title":"Acetylation-mediated fluconazole inactivation: A novel antifungal resistance mechanism","authors":"Ludmila Gouveia-Eufrasio , Gustavo José Cota de Freitas , Danielle Letícia da Silva , Iara Rinco Silva , Daniel Santana de Carvalho , Milton T. Drott , Bruna Carolina Teixeira Almeida , Cesar da Silva Santana Moura , Beatriz Murta Rezende Moraes Ribeiro , Maria Fernanda Liphaus Almeida Negreli , Lucas Cecilio Vilar , Silvia Maria Cordeiro Werneck , Grace Santos Tavares Avelar , Álan Natanael Pereira Gomes , Isabela Lima de Miranda , Mariana Guerra de Aguilar , Rossimiriam Pereira de Freitas , Luana Rossato , Rafael Wesley Bastos , Lívia Kmetzsch , Daniel Assis Santos","doi":"10.1016/j.drup.2026.101359","DOIUrl":"10.1016/j.drup.2026.101359","url":null,"abstract":"<div><div>Antifungal resistance is considered a global health threat. However, enzymatic inactivation of antifungals, a common mechanism seen in antibacterial resistance, has not yet been described in fungi. From a One Health perspective, this study demonstrates that <em>Cryptococcus deuterogattii</em> and <em>C. neoformans</em>, the leading agents of cryptococcosis, enzymatically inactivate fluconazole. Agrochemicals induce the overexpression of genes that code for acetyltransferases, specifically GCN5 and NAT10. These enzymes catalyze the acetylation of fluconazole into <em>O</em>-acetyl-fluconazole. This metabolite is unable to properly bind to 14-α-demethylase, the azole target, abolishing the antifungal activity. GCN5 and NAT10 inhibitors constrained acetylation and restored fluconazole activity, highlighting their potential as therapeutic adjuvants. The same phenotype was observed in other fungal species, suggesting broader relevance. Furthermore, <em>O</em>-acetyl-fluconazole was also detected in cerebrospinal fluid from cryptococcal meningitis patients undergoing fluconazole treatment. These findings reveal a previously unrecognized antifungal resistance mechanism and suggest that environmental traits shape clinically relevant resistance through conserved enzymatic pathways.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101359"},"PeriodicalIF":21.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibitors of cellular RSK isoforms exhibit anti-SARS-CoV-2 activity, enhance efficacy of direct-acting antivirals, and suppress emergence of resistance 细胞RSK亚型抑制剂显示抗sars - cov -2活性，增强直接作用抗病毒药物的疗效，并抑制耐药性的出现

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-21 DOI: 10.1016/j.drup.2026.101357

André Schreiber , Benjamin Ambrosy , Darisuren Anhlan , Stefan Bletz , Alexander Mellmann , Stephan Ludwig

Identifying novel antiviral treatment strategies to expand the existing repertoire of available small-molecule drugs is an important task in addressing both current and emerging viral diseases. Host-targeting antivirals (HTA) and direct-acting antivirals (DAA) represent two classes of such small-molecule drugs. While both classes of drugs are active in a stand-alone treatment, it may be a promising approach to increase the benefits of both by using them in combination which may lead to a synergistic amplification of the antiviral effects. In this study, we show that SARS-CoV-2 is sensitive to the inhibition of the cellular 90 kDa ribosomal S6 kinase (RSK) family, which are direct downstream effectors of the Raf/MEK/ERK signaling pathway. Specific RSK inhibitors (BI-D1870, BRD 7389) showed anti-SARS-CoV-2 properties in single and combination treatment. We could evaluate synergistic properties with the DAAs Remdesivir (RDV) and Nirmatrelvir (NTV). Serial passaging of δ-B.1.617.2 variant under permanent drug pressure did not alter the susceptibility to the RSK inhibitors, while attenuated responsiveness was found for the DAAs. Interestingly, this diminished drug sensitivity did not occur when BRD 7389 and NTV were combined. Furthermore, we demonstrated that combining RSK inhibitors with DAAs not only helps prevent the development of reduced drug susceptibility but may also synergistically compensate for diminished DAA sensitivity, a phenotype that was not found for combined DAA (NTV + RDV) treatments. These results are indicative of the potency and benefit of a combination treatment with DAAs and HTAs, which may likely be the basis for safe and long-lasting novel antiviral therapeutic approaches.

确定新的抗病毒治疗策略以扩大现有的可用小分子药物库是解决当前和新出现的病毒性疾病的重要任务。宿主靶向抗病毒药物（HTA）和直接作用抗病毒药物（DAA）是这类小分子药物的两类。虽然这两类药物在单独治疗中都是有效的，但通过联合使用它们来增加两者的益处可能是一种有希望的方法，这可能会导致抗病毒效果的协同放大。在这项研究中，我们发现SARS-CoV-2对细胞90 kDa核糖体S6激酶（RSK）家族的抑制敏感，RSK家族是Raf/MEK/ERK信号通路的直接下游效应器。特异性RSK抑制剂（BI-D1870、BRD 7389）在单独和联合治疗中均表现出抗sars - cov -2的特性。我们可以评估与DAAs Remdesivir （RDV）和Nirmatrelvir （NTV）的协同特性。δ-B.1.617.2变异在持续药物压力下的连续传代没有改变对RSK抑制剂的敏感性，而DAAs的反应性减弱。有趣的是，当BRD 7389和NTV联合使用时，这种药物敏感性没有降低。此外，我们证明RSK抑制剂与DAAs联合不仅有助于防止药物敏感性降低的发展，而且还可以协同补偿DAA敏感性降低，这是DAA （NTV + RDV）联合治疗中没有发现的表型。这些结果表明了DAAs和hta联合治疗的效力和益处，这可能是安全和持久的新型抗病毒治疗方法的基础。

{"title":"Inhibitors of cellular RSK isoforms exhibit anti-SARS-CoV-2 activity, enhance efficacy of direct-acting antivirals, and suppress emergence of resistance","authors":"André Schreiber , Benjamin Ambrosy , Darisuren Anhlan , Stefan Bletz , Alexander Mellmann , Stephan Ludwig","doi":"10.1016/j.drup.2026.101357","DOIUrl":"10.1016/j.drup.2026.101357","url":null,"abstract":"<div><div>Identifying novel antiviral treatment strategies to expand the existing repertoire of available small-molecule drugs is an important task in addressing both current and emerging viral diseases. Host-targeting antivirals (HTA) and direct-acting antivirals (DAA) represent two classes of such small-molecule drugs. While both classes of drugs are active in a stand-alone treatment, it may be a promising approach to increase the benefits of both by using them in combination which may lead to a synergistic amplification of the antiviral effects. In this study, we show that SARS-CoV-2 is sensitive to the inhibition of the cellular 90 kDa ribosomal S6 kinase (RSK) family, which are direct downstream effectors of the Raf/MEK/ERK signaling pathway. Specific RSK inhibitors (BI-D1870, BRD 7389) showed anti-SARS-CoV-2 properties in single and combination treatment. We could evaluate synergistic properties with the DAAs Remdesivir (RDV) and Nirmatrelvir (NTV). Serial passaging of δ-B.1.617.2 variant under permanent drug pressure did not alter the susceptibility to the RSK inhibitors, while attenuated responsiveness was found for the DAAs. Interestingly, this diminished drug sensitivity did not occur when BRD 7389 and NTV were combined. Furthermore, we demonstrated that combining RSK inhibitors with DAAs not only helps prevent the development of reduced drug susceptibility but may also synergistically compensate for diminished DAA sensitivity, a phenotype that was not found for combined DAA (NTV + RDV) treatments. These results are indicative of the potency and benefit of a combination treatment with DAAs and HTAs, which may likely be the basis for safe and long-lasting novel antiviral therapeutic approaches.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101357"},"PeriodicalIF":21.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deciphering the roles of AcrAB-TolC efflux pump in promoting the transmission of antibiotic resistance 解读acrabb - tolc外排泵在促进抗生素耐药性传播中的作用

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-01-19 DOI: 10.1016/j.drup.2026.101358

Shuyao Zhu , Feiyu Yu , Bingqing Yang , Miao Zhang , Haijie Zhang , Zhiqiang Wang , Yuan Liu

Plasmid-mediated conjugative transfer drives the global dissemination of antimicrobial resistance, posing a global threat to public health. Besides extruding antibiotics, bacterial multidrug efflux pumps modulate virulence, yet their influence on resistance plasmid spread in antibiotic-free settings remains undefined. Herein, we demonstrate that the AcrAB-TolC efflux pump is critical for the horizontal transfer of model plasmid RP4–7 and diverse clinical resistance plasmids. Single deletions of acrA, acrB or tolC significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that acrB deficiency reduces interbacterial contact, diminishes energy metabolism, and impairs activity of the glutamate decarboxylase, quorum sensing and the conjugative systems. Furthermore, we identify chlorpromazine as a potential AcrB ligand, which blocks plasmid transfer both in vivo and in vitro. Collectively, our findings reveal the role of efflux pumps in plasmid transfer and underscore AcrB as a druggable target to curtail the spread of antibiotic resistance.

质粒介导的结合转移推动了抗菌素耐药性的全球传播，对公共卫生构成全球性威胁。除了挤出抗生素外，细菌多药外排泵还调节毒力，但它们对无抗生素环境中耐药质粒传播的影响仍不清楚。在此，我们证明acrabb - tolc外排泵对于模型质粒RP4-7和各种临床耐药质粒的水平转移至关重要。acrA， acrB或tolC的单个缺失显著减少质粒转移，并且互补完全恢复共轭频率到控制水平。机制研究表明，acrB缺乏减少了细菌间的接触，减少了能量代谢，损害了谷氨酸脱羧酶、群体感应和共轭系统的活性。此外，我们发现氯丙嗪是一种潜在的AcrB配体，可以在体内和体外阻断质粒转移。总的来说，我们的研究结果揭示了外排泵在质粒转移中的作用，并强调AcrB是一种可抑制抗生素耐药性传播的药物靶点。

{"title":"Deciphering the roles of AcrAB-TolC efflux pump in promoting the transmission of antibiotic resistance","authors":"Shuyao Zhu , Feiyu Yu , Bingqing Yang , Miao Zhang , Haijie Zhang , Zhiqiang Wang , Yuan Liu","doi":"10.1016/j.drup.2026.101358","DOIUrl":"10.1016/j.drup.2026.101358","url":null,"abstract":"<div><div>Plasmid-mediated conjugative transfer drives the global dissemination of antimicrobial resistance, posing a global threat to public health. Besides extruding antibiotics, bacterial multidrug efflux pumps modulate virulence, yet their influence on resistance plasmid spread in antibiotic-free settings remains undefined. Herein, we demonstrate that the AcrAB-TolC efflux pump is critical for the horizontal transfer of model plasmid RP4–7 and diverse clinical resistance plasmids. Single deletions of <em>acrA</em>, <em>acrB</em> or <em>tolC</em> significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that <em>acrB</em> deficiency reduces interbacterial contact, diminishes energy metabolism, and impairs activity of the glutamate decarboxylase, quorum sensing and the conjugative systems. Furthermore, we identify chlorpromazine as a potential AcrB ligand, which blocks plasmid transfer both <em>in vivo</em> and <em>in vitro</em>. Collectively, our findings reveal the role of efflux pumps in plasmid transfer and underscore AcrB as a druggable target to curtail the spread of antibiotic resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101358"},"PeriodicalIF":21.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Drug Resistance Updates

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀