ACS Infectious Diseases最新文献

High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila─A Comparison. 克鲁斯锥虫、假马勒伯克霍尔德氏菌和嗜肺军团菌巨噬细胞感染潜能蛋白的高亲和力抑制剂──比较。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-10-02 DOI: 10.1021/acsinfecdis.4c00553

Theresa Lohr, Carina Herbst, Nicole M Bzdyl, Christopher Jenkins, Nicolas J Scheuplein, Wisely Oki Sugiarto, Jacob J Whittaker, Albert Guskov, Isobel Norville, Ute A Hellmich, Felix Hausch, Mitali Sarkar-Tyson, Christoph Sotriffer, Ulrike Holzgrabe

{"title":"High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila─A Comparison.","authors":"Theresa Lohr, Carina Herbst, Nicole M Bzdyl, Christopher Jenkins, Nicolas J Scheuplein, Wisely Oki Sugiarto, Jacob J Whittaker, Albert Guskov, Isobel Norville, Ute A Hellmich, Felix Hausch, Mitali Sarkar-Tyson, Christoph Sotriffer, Ulrike Holzgrabe","doi":"10.1021/acsinfecdis.4c00553","DOIUrl":"10.1021/acsinfecdis.4c00553","url":null,"abstract":"Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila, express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion. The affinity of a series of pipecolic acid-type MIP inhibitors was evaluated against all MIPs using a fluorescence polarization assay. The analysis of structure-activity relationships led to highly active inhibitors of MIPs of all pathogens, characterized by a one-digit nanomolar affinity for the MIPs and a very effective inhibition of their peptidyl-prolyl isomerase activity. Docking studies, molecular dynamics simulations, and quantum mechanical calculations suggest an extended σ-hole of the meta-halogenated phenyl sulfonamide to be responsible for the high affinity.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic. 用小干扰 RNA 治疗药物 Imdusiran 控制乙型肝炎病毒

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-22 DOI: 10.1021/acsinfecdis.4c00514

Emily P Thi, Xin Ye, Nicholas M Snead, Amy C H Lee, Holly M Micolochick Steuer, Andrzej Ardzinski, Ingrid E Graves, Christine Espiritu, Andrea Cuconati, Cory Abbott, Agnes Jarosz, Xiaowei Teng, Bhavna Paratala, Kevin McClintock, Troy Harasym, Rene Rijnbrand, Angela M Lam, Michael J Sofia

{"title":"Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic.","authors":"Emily P Thi, Xin Ye, Nicholas M Snead, Amy C H Lee, Holly M Micolochick Steuer, Andrzej Ardzinski, Ingrid E Graves, Christine Espiritu, Andrea Cuconati, Cory Abbott, Agnes Jarosz, Xiaowei Teng, Bhavna Paratala, Kevin McClintock, Troy Harasym, Rene Rijnbrand, Angela M Lam, Michael J Sofia","doi":"10.1021/acsinfecdis.4c00514","DOIUrl":"10.1021/acsinfecdis.4c00514","url":null,"abstract":"Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies. 3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synhesis and Bioimaging Studies.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-26 DOI: 10.1021/acsinfecdis.4c00304

Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y Botté, Stéphanie A Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet

{"title":"3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies.","authors":"Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y Botté, Stéphanie A Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet","doi":"10.1021/acsinfecdis.4c00304","DOIUrl":"10.1021/acsinfecdis.4c00304","url":null,"abstract":"The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, \"clickable\" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

8-Hydroxyquinoline Series Exerts Bactericidal Activity against Mycobacterium tuberculosis Via Copper-Mediated Toxicity. 8-羟基喹啉系列通过铜介导的毒性对结核分枝杆菌具有杀菌活性

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-27 DOI: 10.1021/acsinfecdis.4c00582

Amala Bhagwat, Arielle Butts, Eric Greve, Yan Cheung, Eduard Melief, James Gomez, Deborah T Hung, Tanya Parish

{"title":"8-Hydroxyquinoline Series Exerts Bactericidal Activity against Mycobacterium tuberculosis Via Copper-Mediated Toxicity.","authors":"Amala Bhagwat, Arielle Butts, Eric Greve, Yan Cheung, Eduard Melief, James Gomez, Deborah T Hung, Tanya Parish","doi":"10.1021/acsinfecdis.4c00582","DOIUrl":"10.1021/acsinfecdis.4c00582","url":null,"abstract":"New drugs and mechanisms of action targeting Mycobacterium tuberculosis are urgently needed to solve the global pandemic of tuberculosis. We previously demonstrated that the 8-hydroxyquinoline series has rapid bactericidal activity against M. tuberculosis. In this work, we determined that the activity of the 8HQ series is potentiated by copper ions and that the activity is dependent on copper since activity was reduced when copper was depleted from the medium. We determined that exposure to 8HQs led to an increase in intracellular copper. The increase in copper ions was specific since we saw no changes for other metal cations (zinc, iron, magnesium, manganese, or calcium). We observed the transient generation of reactive oxygen species after 8HQ exposure which disappeared by 24 h. Inhibition of growth could be partially relieved by scavenging hydroxyl radicals. We excluded the possibility that 8HQs are toxic by DNA intercalation. We screened a panel of hypomorph strains and identified sensitized strains. The pattern of sensitized strains did not suggest a specific target, but metalloenzymes, proteins with Fe-S clusters, and cell envelope biosynthetic enzymes were highlighted. These data suggest that 8HQs do not have a specific intracellular target, but act as copper ionophores, and that the mode of action is via copper-dependent toxicity.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

A Review of Antibacterial Candidates with New Modes of Action. 具有新作用模式的抗菌候选药物综述。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-07-17 DOI: 10.1021/acsinfecdis.4c00218

Mark S Butler, Waldemar Vollmer, Emily C A Goodall, Robert J Capon, Ian R Henderson, Mark A T Blaskovich

引用次数: 0

Mycobacterium tuberculosis Suppresses Inflammatory Responses in Host through Its Cholesterol Metabolites. 结核分枝杆菌通过胆固醇代谢物抑制宿主的炎症反应

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-10-03 DOI: 10.1021/acsinfecdis.4c00529

Jing Wu, Yong Zhang, Wenqi Li, Hao Tang, Ying Zhou, Di You, Xiaohe Chu, Hanbing Li, Jinsai Shang, Nan Qi, Bang-Ce Ye

{"title":"Mycobacterium tuberculosis Suppresses Inflammatory Responses in Host through Its Cholesterol Metabolites.","authors":"Jing Wu, Yong Zhang, Wenqi Li, Hao Tang, Ying Zhou, Di You, Xiaohe Chu, Hanbing Li, Jinsai Shang, Nan Qi, Bang-Ce Ye","doi":"10.1021/acsinfecdis.4c00529","DOIUrl":"10.1021/acsinfecdis.4c00529","url":null,"abstract":"Cholesterol is a key carbon source for Mycobacterium tuberculosis (Mtb) survival and persistence within macrophages. However, little is known about the role of cholesterol metabolism by Mtb in host-Mtb interplay. Here, we report the immune suppression mediated by Mtb's cholesterol metabolites. Conducting the cholesterol metabolic profiling and loss-of-function experiments, we show that the cholesterol oxidation products catalyzed by a thiolase FadA5 from Mtb H37Ra, 4-androstenedione (AD), and its derivant 1,4-androstenedione (ADD) inhibit the expression of pro-inflammatory cytokines and thus promote bacterial survival in bone marrow-derived macrophages (BMDMs). Our time-resolved fluorescence resonance energy transfer (TR-FRET)-based screening further identifies the nuclear receptor LXRα as the target of ADD. Activation of LXRα via ADD impedes the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling and reduces cholesterol accumulation in lipid rafts upon TLR4 simulation, thereby compromising the inflammatory responses. Our findings provide the evidence that Mtb could suppress the host immunity through its cholesterol metabolic enzyme and products, which are potential targets for screening novel anti-tuberculosis (TB) agents.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Mycobacterium LacI-type Transcription Regulator Rv3575c Affects Host Innate Immunity by Regulating Bacterial mce4 Operon-Mediated Cholesterol Transport. 分枝杆菌 LacI 型转录调节器 Rv3575c 通过调节细菌 mce4 操作子介导的胆固醇转运影响宿主的先天免疫力

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-05 DOI: 10.1021/acsinfecdis.4c00493

Junfeng Zhen, Yuerigu Abuliken, Yaru Yan, Chaoyun Gao, Zhiyong Jiang, Tingting Huang, Thi Thu Thuy Le, Liying Xiang, Peibo Li, Jianping Xie

{"title":"Mycobacterium LacI-type Transcription Regulator Rv3575c Affects Host Innate Immunity by Regulating Bacterial mce4 Operon-Mediated Cholesterol Transport.","authors":"Junfeng Zhen, Yuerigu Abuliken, Yaru Yan, Chaoyun Gao, Zhiyong Jiang, Tingting Huang, Thi Thu Thuy Le, Liying Xiang, Peibo Li, Jianping Xie","doi":"10.1021/acsinfecdis.4c00493","DOIUrl":"10.1021/acsinfecdis.4c00493","url":null,"abstract":"Mycobacterium tuberculosis has evolved a highly specialized system to snatch essential nutrients from its host, among which host-derived cholesterol has been established as one main carbon source for M. tuberculosis to survive within granulomas. The uptake, catabolism, and utilization of cholesterol are important for M. tuberculosis to sustain within the host largely via remodeling of the bacterial cell walls. However, the regulatory mechanism of cholesterol uptake and its impact on bacterium fate within infected hosts remain elusive. Here, we found that M. tuberculosis LacI-type transcription regulator Rv3575c negatively regulates its mce4 family gene transcription. Overexpression of Rv3575c impaired the utilization of cholesterol as the sole carbon source by Mycobacterium smegmatis, activating the host's innate immune response and triggering cell pyroptosis. The M. smegmatis homologue of Rv3575c MSMEG6044 knockout showed enhanced hydrophobicity and permeability of the cell wall and resistance to ethambutol, suppressed the host innate immune response to M. smegmatis, and promoted the survival of M. smegmatis in macrophages and infected mouse lungs, leading to reduced transcriptional levels of TNFα and IL-6. In summary, these data indicate a role of Rv3575c in the pathogenesis of mycobacteria and reveal the key function of Rv3575c in cholesterol transport in mycobacteria.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Lung Damage Induced by Plasmodium berghei ANKA in Murine Model of Malarial Infection is Mitigated by Dietary Supplementation with DHA-Rich Omega-3. 膳食中补充富含 DHA 的 Omega-3 可减轻疟原虫 ANKA 在小鼠疟疾感染模型中引起的肺损伤。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-20 DOI: 10.1021/acsinfecdis.4c00482

Carolina David-Vieira, Barbara Albuquerque Carpinter, Jéssica Correia Bezerra-Bellei, Letícia Ferreira Machado, Felipe Oliveira Raimundo, Cinthia Magalhães Rodolphi, Daniela Chaves Renhe, Isabella Rodrigues Nogueira Guedes, Fernanda Mikaela Moreira Gonçalves, Ludmila Ponce Monken Custódio Pereira, Marcos Vinicius Rangel Ferreira, Haroldo Lobo Dos Santos Nascimento, Adolfo Firmino Neto, Flávia Lima Ribeiro Gomes, Vinicius Novaes Rocha, Juciane Maria de Andrade Castro, Kézia Katiani Gorza Scopel

{"title":"Lung Damage Induced by Plasmodium berghei ANKA in Murine Model of Malarial Infection is Mitigated by Dietary Supplementation with DHA-Rich Omega-3.","authors":"Carolina David-Vieira, Barbara Albuquerque Carpinter, Jéssica Correia Bezerra-Bellei, Letícia Ferreira Machado, Felipe Oliveira Raimundo, Cinthia Magalhães Rodolphi, Daniela Chaves Renhe, Isabella Rodrigues Nogueira Guedes, Fernanda Mikaela Moreira Gonçalves, Ludmila Ponce Monken Custódio Pereira, Marcos Vinicius Rangel Ferreira, Haroldo Lobo Dos Santos Nascimento, Adolfo Firmino Neto, Flávia Lima Ribeiro Gomes, Vinicius Novaes Rocha, Juciane Maria de Andrade Castro, Kézia Katiani Gorza Scopel","doi":"10.1021/acsinfecdis.4c00482","DOIUrl":"10.1021/acsinfecdis.4c00482","url":null,"abstract":"Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe complications that can occur in infections caused by any Plasmodium species. Due to the high lethality rate and the lack of specific treatment for ALI/ARDS, studies aimed at understanding and searching for treatment strategies for such complications have been fundamental. Here, we investigated the protective role of dietary supplementation with DHA-rich fish oil against lung damage induced by Plasmodium berghei ANKA in a murine model. Our results demonstrated that alveolar vascular damage, lung edema, and histopathological alterations were significantly reduced in mice that received dietary supplementation compared to those that did not receive the supplementation. Furthermore, a significant reduction in the number of CD8+ T lymphocytes, in addition to reduced infiltration of inflammatory cells in the bronchoalveolar lavage fluid was also observed. High levels of IL-10, but not of TNF-α and IFN-γ, were also observed in infected mice that received the supplementation, along with a reduction in local oxidative stress. Together, the data suggest that dietary supplementation with DHA-rich fish oil in malarial endemic areas may help reduce lung damage resulting from the infection, thus preventing worsening of the condition.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent Mycobacterium tuberculosis in Caseum. 回旋酶抑制剂介导的 DNA 双链断裂在杀灭酪氨酸中的非复制持久性结核分枝杆菌中的作用

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-24 DOI: 10.1021/acsinfecdis.4c00499

Priyanka Ashwath, Paulina Osiecki, Danielle Weiner, Laura E Via, Jansy P Sarathy

{"title":"Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent Mycobacterium tuberculosis in Caseum.","authors":"Priyanka Ashwath, Paulina Osiecki, Danielle Weiner, Laura E Via, Jansy P Sarathy","doi":"10.1021/acsinfecdis.4c00499","DOIUrl":"10.1021/acsinfecdis.4c00499","url":null,"abstract":"Tuberculosis is the leading cause of mortality by infectious agents worldwide. The necrotic debris, known as caseum, which accumulates in the center of pulmonary lesions and cavities is home to nonreplicating drug-tolerant Mycobacterium tuberculosis that presents a significant hurdle to achieving a fast and durable cure. Fluoroquinolones such as moxifloxacin are highly effective at killing this nonreplicating persistent bacterial population and boosting TB lesion sterilization. Fluoroquinolones target bacterial DNA gyrase, which catalyzes the negative supercoiling of DNA and relaxes supercoils ahead of replication forks. In this study, we investigated the potency of several other classes of gyrase inhibitors against M. tuberculosis in different states of replication. In contrast to fluoroquinolones, many other gyrase inhibitors kill only replicating bacterial cultures but produce negligible cidal activity against M. tuberculosis in ex vivo rabbit caseum. We demonstrate that while these inhibitors are capable of inhibiting M. tuberculosis gyrase DNA supercoiling activity, fluoroquinolones are unique in their ability to cleave double-stranded DNA at low micromolar concentrations. We hypothesize that double-strand break formation is an important driver of gyrase inhibitor-mediated bactericidal potency against nonreplicating persistent M. tuberculosis populations in the host. This study provides general insight into the lesion sterilization potential of different gyrase inhibitor classes and informs the development of more effective chemotherapeutic options against persistent mycobacterial infections.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

2-Aryl-Benzoimidazoles as Type II NADH Dehydrogenase Inhibitors of Mycobacterium tuberculosis. 2-Aryl-Benzoimidazoles 作为结核分枝杆菌的 II 型 NADH 脱氢酶抑制剂。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-10-03 DOI: 10.1021/acsinfecdis.4c00710

Pallavi Saha, Shashikanta Sau, Nitin Pal Kalia, Deepak K Sharma

{"title":"2-Aryl-Benzoimidazoles as Type II NADH Dehydrogenase Inhibitors of Mycobacterium tuberculosis.","authors":"Pallavi Saha, Shashikanta Sau, Nitin Pal Kalia, Deepak K Sharma","doi":"10.1021/acsinfecdis.4c00710","DOIUrl":"10.1021/acsinfecdis.4c00710","url":null,"abstract":"The nonproton pumping type II NADH dehydrogenase in Mycobacterium tuberculosis is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in Mycobacterium tuberculosis, which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery. Herein, we have screened a commercially available library of drug-like molecules and have identified a hit having a benzimidazole core moiety (6, H37Rv mc26230; minimum inhibitory concentration (MIC) = 16 μg/mL and ATP IC50 = 0.23 μg/mL) interfering with the oxidative phosphorylation pathway. Extensive medicinal chemistry optimization resulted in analogue 8, with MIC = 4 μg/mL and ATP IC50 = 0.05 μg/mL against the H37Rv mc26230 strain of Mycobacterium tuberculosis. Compounds 6 and 8 were found to be active against mono- and multidrug-resistant mycobacterium strains and demonstrated a bactericidal response. The Peredox-mCherry experiment and identification of single-nucleotide polymorphisms in mutants of CBR-5992 (a known type II NADH dehydrogenase inhibitor) were used to confirm the molecules as inhibitors of the type II NADH dehydrogenase enzyme. The safety index >10 for the test active molecules revealed the safety of test molecules.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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