ACS Infectious Diseases最新文献_第10页

Discovery of First-in-Class Inhibitors Targeting a Pathogen-Associated Aminoglycoside-Resistance 16S rRNA Methyltransferase 一类针对病原体相关氨基糖苷耐药16S rRNA甲基转移酶的抑制剂的发现

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-11 DOI: 10.1021/acsinfecdis.5c00297

Debayan Dey, Benjamin E. Deprez, Natalia Zelinskaya, Jose M. Castro, William M. Wuest* and Graeme L. Conn*,

{"title":"Discovery of First-in-Class Inhibitors Targeting a Pathogen-Associated Aminoglycoside-Resistance 16S rRNA Methyltransferase","authors":"Debayan Dey, Benjamin E. Deprez, Natalia Zelinskaya, Jose M. Castro, William M. Wuest* and Graeme L. Conn*, ","doi":"10.1021/acsinfecdis.5c00297","DOIUrl":"10.1021/acsinfecdis.5c00297","url":null,"abstract":"Among several distinct mechanisms used by bacteria to circumvent antibiotic stress, a predominant form of resistance to ribosome-targeting compounds is the methylation of their ribosomal RNA (rRNA) binding sites. The acquisition of aminoglycoside-resistance methyltransferases that modify 16S rRNA nucleotides in the ribosome decoding center, for example, results in exceptionally high-level aminoglycoside resistance and poses a major threat to their future clinical utility. Here, we report the discovery of a first-in-class panel of small-molecule inhibitors that target a previously unexploited composite “Y-shaped” binding pocket that is unique to the 30S subunit (substrate)-bound form of the 16S rRNA (m1A1408) methyltransferase NpmA. This Y-shaped pocket, formed by the conserved S-adenosyl-l-methionine binding site and a channel in which A1408 is positioned for modification, was predicted by molecular dynamics simulations to be accessible and potentially druggable in the free enzyme. We therefore conducted high-throughput virtual screening of over 2 million compounds, followed by precision docking and chemoinformatics to select lead scaffolds for initial testing. Iterative experimental analysis and docking of analogs to top hits led to the discovery of three compounds with comparable NpmA inhibitory activity and other similar analogs unable to inhibit the enzyme. Structure–activity relationship analysis highlighted the importance of stereoselectivity, halogen−π interactions, and water-mediated binding. Our strategy provides a new model for methyltransferase inhibitor development, targeting conformationally adaptive and composite binding sites and could be applied to efforts to develop inhibitors of other clinically prevalent resistance determinants such as the aminoglycoside-resistance m7G1045 methyltransferases (e.g., RmtB).","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2276–2286"},"PeriodicalIF":3.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-07-11

Varadharajan Sundaramurthy, and , Erick Strauss,

引用次数: 0

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-07-11

引用次数: 0

Functional Phenotyping of MMV Pandemic Response Box Identifies Stage and Mechanism-Specific Inhibitors against Blood Stage Plasmodium falciparum MMV大流行反应箱的功能表型鉴定阶段和机制特异性抑制剂对抗血期恶性疟原虫。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-11 DOI: 10.1021/acsinfecdis.5c00319

Akhila T.P., Darsana K.M. and Rajesh Chandramohanadas*,

{"title":"Functional Phenotyping of MMV Pandemic Response Box Identifies Stage and Mechanism-Specific Inhibitors against Blood Stage Plasmodium falciparum","authors":"Akhila T.P., Darsana K.M. and Rajesh Chandramohanadas*, ","doi":"10.1021/acsinfecdis.5c00319","DOIUrl":"10.1021/acsinfecdis.5c00319","url":null,"abstract":"Widespread drug resistance necessitates the prioritization of novel scaffolds with alternate mechanisms as possible partner drugs to artemisinin to combat malaria. We utilized the Pandemic Response Box chemical library of the Medicines for Malaria Venture, launched in 2019, to identify inhibitors with stage-specific potency and phenotypic signatures against the blood stage development of Plasmodium falciparum (P. falciparum) toward exploring drug repurposing. From this screening, we initially identified 60 molecules active at 10 μM against both drug-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum. Furthermore, 28 compounds active below 3 μM were prioritized, several of which specifically impaired stage transitions of ring (MMV001014), trophozoite (MMV1593540 and MMV1634402), and schizonts (MMV1580844, MMV1580496, MMV1580173, and MMV1580483), confirmed through microscopic phenotypes and flow cytometry. The ring stage inhibitor, MMV001014, was irreversible, led to no recrudescence, and showed antagonistic effects with artemisinin, indicative of overlapping mechanisms. Both the trophozoite inhibitors, MMV1593540 and MMV1634402, exhibited nanomolar EC50, among which MMV1593540 was additive with artemisinin while antagonistic with chloroquine. Two of the schizont stage inhibitors (MMV1580844 and MMV1580173) appeared to operate through a mechanism driven by the generation of reactive oxygen species, and all of them with molecule-specific effects on infected red blood cell (iRBC) membrane integrity, confirmed through confocal microscopy. Taken together, these results highlight interesting starting points with likely unique modes of action from MMV’s pandemic response box for drug repurposing to combat human malaria that continues to impact the developing world.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2310–2322"},"PeriodicalIF":3.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606821","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

Sialic Acid-Containing Glycolipids Extend the Receptor Repertoire of Enterovirus-D68 含唾液酸的糖脂扩展了肠病毒- d68的受体库。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-09 DOI: 10.1021/acsinfecdis.5c00063

Ashley K. Pereirinha da Silva, Jacobus P. van Trijp, Anouk Montenarie, Jelle A. Fok, Syriam Sooksawasdi Na Ayudhya, Roland J. Pieters, Geert-Jan Boons, Debby van Riel, Robert P. de Vries* and Lisa Bauer*,

{"title":"Sialic Acid-Containing Glycolipids Extend the Receptor Repertoire of Enterovirus-D68","authors":"Ashley K. Pereirinha da Silva, Jacobus P. van Trijp, Anouk Montenarie, Jelle A. Fok, Syriam Sooksawasdi Na Ayudhya, Roland J. Pieters, Geert-Jan Boons, Debby van Riel, Robert P. de Vries* and Lisa Bauer*, ","doi":"10.1021/acsinfecdis.5c00063","DOIUrl":"10.1021/acsinfecdis.5c00063","url":null,"abstract":"Enterovirus D68 (EV-D68) emerged as a pathogen of increasing health concern globally, particularly due to its association with outbreaks of severe respiratory diseases and acute flaccid myelitis (AFM) in children. Knowledge regarding the tissue tropism and pathogenesis of EV-D68 within the respiratory tract and central nervous system remains limited, primarily due to an incomplete understanding of the host factors that facilitate the entry of EV-D68 into host cells. Several cellular receptors involved in EV-D68 infections have been identified, including ICAM-5, sialylated glycoproteins, and heparan sulfate (HS). Here, we investigate the receptor requirement of a panel of EV-D68 strains covering all clades, focusing on HS and sialosides utilizing glycan arrays. We found that all EV-D68 strains binding to HS harbor a cell culture adaptive substitution in the structural protein VP1 at position 271, which changes the amino acid into a positively charged one. Glycan array analyses revealed that EV-D68 strains prefer α2,6-linked sialic acids presented on N-glycans, α2,8-linked sialic acids on gangliosides, or both. Inhibition of glycolipid biosynthesis or multivalent glycolipid mimics confirmed that ganglioside structures serve as entry receptors for certain EV-D68 strains. Lastly, we examined whether EV-D68 strains that bind to HS or glycolipids require different uncoating mechanisms. Bafilomycin A1 minimally affected the cell entry of HS-binding EV-D68 strains B2/039 and B2/947, and the ganglioside preferring B1/2013 and other viruses were strongly inhibited. Together, we identified that EV-D68 strains can use disialoglycolipids as novel receptors and that different EV-D68 strains show a promiscuous sialic acid binding repertoire.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2090–2103"},"PeriodicalIF":3.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Membrane Expression Enhances Folding, Multimeric Structure Formation, and Immunogenicity of Viral Capsid Proteins 膜表达增强病毒衣壳蛋白的折叠、多聚体结构形成和免疫原性。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-09 DOI: 10.1021/acsinfecdis.5c00067

Junru Cui, Fangfeng Yuan, Jane Qin, Ju Hyeong Jeon, Dong Soo Yun, Tianlei Wang, Renhuan Xu, Hong Cao, Ashleigh A. Tungate, Christopher L. Netherton and Jianzhu Chen*,

{"title":"Membrane Expression Enhances Folding, Multimeric Structure Formation, and Immunogenicity of Viral Capsid Proteins","authors":"Junru Cui, Fangfeng Yuan, Jane Qin, Ju Hyeong Jeon, Dong Soo Yun, Tianlei Wang, Renhuan Xu, Hong Cao, Ashleigh A. Tungate, Christopher L. Netherton and Jianzhu Chen*, ","doi":"10.1021/acsinfecdis.5c00067","DOIUrl":"10.1021/acsinfecdis.5c00067","url":null,"abstract":"Viral capsid proteins are widely explored for subunit vaccine development but are often hampered by their complexity of production and low immunogenicity. Here, we report a simple approach to overcoming these challenges by combining mRNA vaccine technology with protein engineering. Using African swine fever virus (ASFV) capsid proteins P72 and penton as models, we engineered them into membrane-bound and secreted forms and compared their immunogenicity to that of the native intracellular form in mice and pigs through mRNA vaccination. The membrane-bound and secreted P72 and penton folded into their native multimeric structure independent of the viral chaperone, therefore preserving their conformational epitopes. The membrane-bound P72 and penton also elicited significantly stronger antibody and T cell responses than their secreted or intracellular counterparts. Our study provides a simple approach to enhancing folding, multimeric structure formation, and immunogenicity of viral capsid proteins for ASFV subunit vaccine development and immunogenicity of intracellular proteins in general.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2104–2115"},"PeriodicalIF":3.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598895","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

Interactions between Lipopolysaccharide and Peptide Bacteriocin BacSp222 Influence Their Biological Activities 脂多糖与肽细菌素BacSp222的相互作用影响其生物活性。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-08 DOI: 10.1021/acsinfecdis.5c00066

Justyna Śmiałek-Bartyzel, Monika Bzowska, Alicja Frączek, Iwona Wojda, Renata Mężyk-Kopeć, Piotr Bonarek, Artur Blat, Jan Rak and Paweł Mak*,

{"title":"Interactions between Lipopolysaccharide and Peptide Bacteriocin BacSp222 Influence Their Biological Activities","authors":"Justyna Śmiałek-Bartyzel, Monika Bzowska, Alicja Frączek, Iwona Wojda, Renata Mężyk-Kopeć, Piotr Bonarek, Artur Blat, Jan Rak and Paweł Mak*, ","doi":"10.1021/acsinfecdis.5c00066","DOIUrl":"10.1021/acsinfecdis.5c00066","url":null,"abstract":"This study describes the interactions between two different pro-inflammatory factors produced by bacteria, lipopolysaccharide (LPS) from Gram-negative bacteria and the peptide BacSp222 produced by a Gram-positive zoonotic strain, Staphylococcus pseudintermedius 222. We demonstrate that the mentioned molecules interact, forming a complex, and this phenomenon selectively reduces their biological activities in vitro and in vivo. Specifically, the levels of tumor necrosis factor (TNF) and nitric oxide (NO) produced by monocyte-macrophage cells were lower in samples treated with both LPS and BacSp222 compared to those treated with LPS alone. This is most likely because BacSp222 limited the ability of LPS to stimulate the TLR4 receptor. In the Galleria mellonella larvae injected simultaneously with LPS and BacSp222, the activity of hemolymph phenoloxidase, a key component of the insect immune response, was lower than that observed in larvae injected with either LPS or BacSp222 alone. Moreover, LPS inhibited the antibacterial activity of the bacteriocin, while BacSp222 limited LPS’s ability to activate a proenzyme in the Limulus amebocyte lysate test. The changes in the activities of BacSp222 and LPS were attributed to the electrostatic interactions between LPS micelles and bacteriocin molecules, resulting in a decrease in LPS aggregate size and the direct formation of a complex between them, as revealed by gel filtration and isothermal microcalorimetry.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2116–2130"},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of IMT-P8 on the Efficacy of Conventional Antibiotics for the Treatment of Drug-Resistant and Intracellular Staphylococcus aureus IMT-P8对常规抗生素治疗耐药及细胞内金黄色葡萄球菌疗效的影响

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-05 DOI: 10.1021/acsinfecdis.5c00278

Vidhu Singh, Sharmila Talukdar, Niharika Nirwal, Manoj Raje, Prabhat Ranjan Mishra and Hemraj Nandanwar*,

{"title":"Impact of IMT-P8 on the Efficacy of Conventional Antibiotics for the Treatment of Drug-Resistant and Intracellular Staphylococcus aureus","authors":"Vidhu Singh, Sharmila Talukdar, Niharika Nirwal, Manoj Raje, Prabhat Ranjan Mishra and Hemraj Nandanwar*, ","doi":"10.1021/acsinfecdis.5c00278","DOIUrl":"10.1021/acsinfecdis.5c00278","url":null,"abstract":"Addressing the issue of antimicrobial resistance is of the utmost importance on a global scale. We are in dire need of innovative methods and alternatives to new antibiotic discovery in order to address the growing problem of antimicrobial resistance. In this study, we investigated the efficacy of cell-penetrating peptide (IMT-P8) as an adjuvant to enhance the activity of conventional antibiotics against multidrug-resistant and intracellular Staphylococcus aureus in vitro and in vivo. IMT-P8 potentiates various antibiotics belonging to different classes. The best combination was found with clarithromycin; IMT-P8 modulated its activity by 256-fold. The IMT-P8 + clarithromycin combination showed excellent antibiofilm and intracellular pathogen-killing activity against MRSA GMCH 839. The remarkable effectiveness of IMT-P8 was demonstrated in murine superficial skin infection and sepsis survival models. The safety studies show that IMT-P8 exhibits no toxicity at its effective concentration in vitro and in vivo. These findings suggest that IMT-P8 could be a promising antibiotic adjuvant for treating severe bacterial infections caused by MRSA.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2232–2245"},"PeriodicalIF":3.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566847","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

Design, Synthesis, and Antibacterial Evaluation of Rifampicin–Siderophore Conjugates 利福平-硫铁酚缀合物的设计、合成及抗菌评价。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-05 DOI: 10.1021/acsinfecdis.5c00311

Vladyslav Lysenko, Mei-Ling Gao, Fabienne A. C. Sterk, Paolo Innocenti, Cornelis J. Slingerland and Nathaniel I. Martin*,

{"title":"Design, Synthesis, and Antibacterial Evaluation of Rifampicin–Siderophore Conjugates","authors":"Vladyslav Lysenko, Mei-Ling Gao, Fabienne A. C. Sterk, Paolo Innocenti, Cornelis J. Slingerland and Nathaniel I. Martin*, ","doi":"10.1021/acsinfecdis.5c00311","DOIUrl":"10.1021/acsinfecdis.5c00311","url":null,"abstract":"The growing concern over antibiotic resistance has sparked increased attention toward developing alternative antibiotic strategies. One promising approach, known as the “Trojan horse” strategy, involves the use of siderophores to hijack bacteria’s iron transport systems as a way of delivering antibiotics inside the bacterial cell. This method is particularly promising in tackling Gram-negative bacteria, which have an outer membrane that many antibiotics cannot penetrate. One such antibiotic is rifampicin, a drug used to treat tuberculosis and infections caused by Gram-positive bacteria. Although rifampicin binds to a highly conserved bacterial RNA subunit, its activity is generally poor against Gram-negative bacteria due to their outer membrane. Aiming to expand rifampicin’s efficacy, we here report the design and synthesis of several rifampicin–siderophore conjugates that exhibit enhanced activity against Gram-negative pathogens. Our findings indicate that the structural features of both the linker and catechol are crucial for the activity of conjugates with compound 33, wherein rifampicin is connected to chlorocatechol via a short ester linker, showing an up to 32-fold improvement in activity.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 8","pages":"2301–2309"},"PeriodicalIF":3.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tranylcypromine-Based LSD1 Inhibitors as Useful Agents to Reduce Viability of Schistosoma mansoni 基于tranylcylers的LSD1抑制剂作为降低曼氏血吸虫活力的有效药物。

IF 3.8 2区医学

ACS Infectious Diseases Pub Date : 2025-07-02 DOI: 10.1021/acsinfecdis.5c00224

Emanuele Fabbrizi, Gebremedhin Solomon Hailu, A. Ganesan, Rossella Fioravanti*, Clemens Zwergel, Chiara Lambona, Sergio Valente, Giulia Fianco, Angela Iuzzolino, Daniela Trisciuoglio, Jonatan Caroli, Andrea Mattevi, Cécile Häberli, Jennifer Keiser, Dante Rotili* and Antonello Mai,

引用次数: 0