ACS Infectious Diseases最新文献_第4页

Multifunctional Mycobacterial Topoisomerases with Distinctive Features. 具有独特特征的多功能分枝杆菌拓扑异构酶。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-14 Epub Date: 2025-01-18 DOI: 10.1021/acsinfecdis.4c00880

Iqball Faheem, Valakunja Nagaraja

{"title":"Multifunctional Mycobacterial Topoisomerases with Distinctive Features.","authors":"Iqball Faheem, Valakunja Nagaraja","doi":"10.1021/acsinfecdis.4c00880","DOIUrl":"10.1021/acsinfecdis.4c00880","url":null,"abstract":"Tuberculosis (TB) continues to be a major cause of death worldwide despite having an effective combinatorial therapeutic regimen and vaccine. Being one of the most successful human pathogens, Mycobacterium tuberculosis retains the ability to adapt to diverse intracellular and extracellular environments encountered by it during infection, persistence, and transmission. Designing and developing new therapeutic strategies to counter the emergence of multidrug-resistant and extensively drug-resistant TB remains a major task. DNA topoisomerases make up a unique class of ubiquitous enzymes that ensure steady-state level supercoiling and solve topological problems occurring during DNA transactions in cells. They continue to be attractive targets for the discovery of novel classes of antibacterials and to develop better molecules from existing drugs by virtue of their reaction mechanism. The limited repertoire of topoisomerases in M. tuberculosis, key differences in their properties compared to topoisomerases from other bacteria, their essentiality for the pathogen's survival, and validation as candidates for drug discovery provide an opportunity to exploit them in drug discovery efforts. The present review provides insights into their organization, structure, function, and regulation to further efforts in targeting them for new inhibitor discovery. First, the structure and biochemical properties of DNA gyrase and Topoisomerase I (TopoI) of mycobacteria are described compared to the well-studied counterparts from other bacteria. Next, we provide an overview of known inhibitors of DNA gyrase and emerging novel bacterial topoisomerase inhibitors (NBTIs). We also provide an update on TopoI-specific compounds, highlighting mycobacteria-specific inhibitors.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"366-385"},"PeriodicalIF":4.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995994","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

Pharmacokinetic and Pharmacodynamics of Clofazimine Nano-in-Microparticles: Enhanced Brain Delivery and CNS Tuberculosis Amelioration via Intranasal Administration. 氯唑明纳米微粒的药代动力学和药效学：通过鼻内给药增强脑部给药和改善中枢神经系统结核病。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-13 DOI: 10.1021/acsinfecdis.4c00767

Krishna Jadhav, Agrim Jhilta, Raghuraj Singh, Swarnima Negi, Shweta Sharma, Rahul Shukla, Amit Kumar Singh, Rahul Kumar Verma

{"title":"Pharmacokinetic and Pharmacodynamics of Clofazimine Nano-in-Microparticles: Enhanced Brain Delivery and CNS Tuberculosis Amelioration via Intranasal Administration.","authors":"Krishna Jadhav, Agrim Jhilta, Raghuraj Singh, Swarnima Negi, Shweta Sharma, Rahul Shukla, Amit Kumar Singh, Rahul Kumar Verma","doi":"10.1021/acsinfecdis.4c00767","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00767","url":null,"abstract":"Mycobacterium tuberculosis (Mtb) demonstrates a proclivity for infecting extrapulmonary sites, notably the brain. Treating these extrapulmonary tuberculosis (TB) manifestations is challenging due to the difficulty of drug delivery across the blood-brain barrier. Clofazimine (CLF) has exhibited promising activity against Mtb, including multidrug-resistant variants, in vitro and in preclinical animal models. However, its clinical implication is restricted owing to poor physicochemical and pharmacokinetic properties. This study aims to develop CLF nano-in-microparticles (CLF-NIMs) for brain drug delivery for central nervous system TB (CNS-TB) treatment via the intranasal route. Simultaneously, the potential dissemination of TB bacilli to the brain was investigated. Following treatment, colony-forming unit (CFU) enumeration was conducted in both the brain and lung tissues to assess mycobacterial burden. Concurrently, drug concentrations were quantified in serum, brain, and lung tissue, enabling a comprehensive evaluation of pharmacokinetics and tissue-specific drug distribution. In pharmacokinetic investigations of CLF-NIMs, significant accumulation of CLF was observed in brain tissue compared to orally administered CLF, surpassing the minimum inhibitory concentration of CLF. In a murine CNS-TB model, intranasal insufflation of CLF-NIMs for 4 weeks led to a substantial reduction (∼0.99 ± 0.57 Log10CFU/gram) in CFU count in the brain compared to oral administration of CLF (2.45 ± 0.47 Log10CFU/gram). These promising preclinical results indicate that CLF-NIMs are well-tolerated and exhibit significant anti-TB activity in a murine CNS-TB model.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412305","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

Anti-Intracellular MRSA Activity of Antibiotic-Loaded Lipid-Polymer Hybrid Nanoparticles and Their Effectiveness in Murine Skin Wound Infection Models. 抗生素负载脂质聚合物混合纳米粒子的抗细胞内 MRSA 活性及其在小鼠皮肤伤口感染模型中的有效性

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-13 DOI: 10.1021/acsinfecdis.4c01016

Wenrui Li, Chuan Hao Tan, Jong-Suep Baek, Lai Jiang, Noele Kai Jing Ng, Kelvin Kian Long Chong, Jun Jie Wong, Liheng Gao, Kimberly A Kline, Say Chye Joachim Loo

{"title":"Anti-Intracellular MRSA Activity of Antibiotic-Loaded Lipid-Polymer Hybrid Nanoparticles and Their Effectiveness in Murine Skin Wound Infection Models.","authors":"Wenrui Li, Chuan Hao Tan, Jong-Suep Baek, Lai Jiang, Noele Kai Jing Ng, Kelvin Kian Long Chong, Jun Jie Wong, Liheng Gao, Kimberly A Kline, Say Chye Joachim Loo","doi":"10.1021/acsinfecdis.4c01016","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01016","url":null,"abstract":"Methicillin-resistant Staphylococcus aureus (MRSA) is a significant concern for skin and soft tissue infections. Apart from biofilm formation, these bacteria can reside intracellularly in phagocytic and nonphagocytic mammalian cells, complicating treatment with conventional antibiotics. Lipid-polymer hybrid nanoparticle (LPN) systems, combining the advantages of polymeric nanoparticles and liposomes, represent a new generation of nanocarriers with the potential to address these therapeutic challenges. In this study, gentamicin (Gen) and vancomycin (Van) were encapsulated in LPNs and evaluated for their ability to eliminate intracellular MRSA in phagocytic macrophage RAW-Blue cells and nonphagocytic epithelial HaCaT cells. Compared to free antibiotics at 100 μg/mL, LPN formulations significantly reduced intracellular bacterial loads in both cell lines. Specifically, LPN-Van resulted in approximately 0.7 Log CFU/well reduction in RAW-Blue cells and 0.3 Log CFU/well reduction in HaCaT cells. LPN-Gen showed a more pronounced reduction, with approximately 1.26 Log CFU/well reduction in RAW-Blue cells and 0.45 Log CFU/well reduction in HaCaT cells. In vivo, LPN-Van at 500 μg/mL significantly reduced MRSA biofilm viability compared to untreated controls (p < 0.001), achieving 98% eradication based on median values. In comparison, free vancomycin achieved a nonstatistically significant 79.2% reduction in biofilm viability compared to control. Prophylactically, LPN-Van at 500 μg/mL decreased MRSA levels to the limit of detection, resulting in a ∼3.5 Log reduction in the median CFU/wound compared to free vancomycin. No acute dermal toxicity was observed for LPN-Van based on histological analysis. These data indicate that LPNs show promise as a drug delivery platform technology to address intracellular infections.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412303","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

Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-12 DOI: 10.1021/acsinfecdis.4c00666

Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins

{"title":"Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.","authors":"Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins","doi":"10.1021/acsinfecdis.4c00666","DOIUrl":"10.1021/acsinfecdis.4c00666","url":null,"abstract":"Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397487","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

High-Throughput Repurposing Screen Reveals Compounds with Activity against Toxoplasma gondii Bradyzoites.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-11 DOI: 10.1021/acsinfecdis.4c00689

Taher Uddin, Jing Xia, Yong Fu, Case W McNamara, Arnab K Chatterjee, L David Sibley

{"title":"High-Throughput Repurposing Screen Reveals Compounds with Activity against Toxoplasma gondii Bradyzoites.","authors":"Taher Uddin, Jing Xia, Yong Fu, Case W McNamara, Arnab K Chatterjee, L David Sibley","doi":"10.1021/acsinfecdis.4c00689","DOIUrl":"10.1021/acsinfecdis.4c00689","url":null,"abstract":"Toxoplasma gondii causes widespread chronic infections that are not cured by current treatments due to the inability to affect semidormant bradyzoite stages within tissue cysts. To identify compounds to eliminate chronic infection, we developed an HTS using a recently characterized strain of T. gondii that undergoes efficient conversion to bradyzoites in vitro. Stage-specific expression of luciferase was used to selectively monitor the growth inhibition of bradyzoites by the Library of Pharmacological Active Compounds, consisting of 1280 drug-like compounds. We identified 44 compounds with >50% inhibitory effects against bradyzoites, including new highly potent compounds, several of which have precedent for antimicrobial activity. Subsequent characterization of the compound sanguinarine sulfate revealed potent and rapid killing against in vitro-produced bradyzoites and bradyzoites harvested from chronically infected mice, including potent activity against intact cysts. These findings provide a platform for expanded screening and identify promising compounds for further preclinical development against T. gondii bradyzoites that are responsible for chronic infection.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397485","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

AHM-1: An Inclusion to the Arsenal of β-Lactam Resistance in Clostridioides difficile.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-07 DOI: 10.1021/acsinfecdis.4c00741

Abirlal Mukherjee, Jyoti Barman, Chandrachur Ghosh, Rajsekhar Adhikary, Kunal Dhankhar, Partha Roy, Sulagna Basu, Saugata Hazra

{"title":"AHM-1: An Inclusion to the Arsenal of β-Lactam Resistance in Clostridioides difficile.","authors":"Abirlal Mukherjee, Jyoti Barman, Chandrachur Ghosh, Rajsekhar Adhikary, Kunal Dhankhar, Partha Roy, Sulagna Basu, Saugata Hazra","doi":"10.1021/acsinfecdis.4c00741","DOIUrl":"10.1021/acsinfecdis.4c00741","url":null,"abstract":"This study delves into a newly discovered MBL (metallo-β-lactamase) in Clostridioides difficile, a formidable pathogen known for causing nosocomial infections and exhibiting resistance to antimicrobial agents. The primary objective was to unravel its structure-function relationship. This research establishes the enzyme AHM-1 as a subclass B3-like MBL. Experimental results reveal that the enzyme's active site consists of two Zn2+ atoms exhibiting tetrahedral and trigonal bipyramidal coordination, similar to B1 and B3 MBLs. Notably, within its active site, it exhibits a lower binding capacity for other transition metal ions such as Fe2+, Mn2+, and Ni2+ compared to Zn2+. The zinc-binding sites of B1 and B3 MBLs contain strictly conserved His116-His118-His196 and Asp120-Cys221/His121-His263. The absence of all the conserved residues except His116, Asp120, and His121 in the Zn-binding site distinctly separates this enzyme from these two MBL subclasses. Conserved zinc binding motifs present in B1 and B3 MBLs are H-X-H-X-D and H-X-H-X-D-H, respectively. The presence of the H-X-D-X-D-H motif in the enzyme, similar to that in B3 enzymes, along with sequence and structural analysis, places this new enzyme closer to the enzymes belonging to the B3 subclass. This study also identifies the likely catalytic residues responsible for its β-lactamase activity, similar to B3 MBLs. In contrast to MBLs, this enzyme displays hydrolytic activity toward aztreonam. It also shows higher catalytic efficiency toward higher generation cephalosporins. This study thus underscores the significance of a novel enzyme with β-lactamase activity in Clostridioides difficile, highlighting its potential implications for clinical treatment due to its disparities from conventional MBLs.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363254","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

Thiazole Derivatives as Promising Candidates for Cryptococcosis Therapy.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-07 DOI: 10.1021/acsinfecdis.4c00732

Victor Augusto Teixeira Leocádio, Isabela L Miranda, Martha H C Magalhães, Valtair Severino Dos Santos Júnior, José Eduardo Goncalves, Renata Barbosa Oliveira, Vinicius Gonçalves Maltarollo, Rafael Wesley Bastos, Gustavo Goldman, Susana Johann, Nalu Teixeira de Aguiar Peres, Daniel de Assis Santos

{"title":"Thiazole Derivatives as Promising Candidates for Cryptococcosis Therapy.","authors":"Victor Augusto Teixeira Leocádio, Isabela L Miranda, Martha H C Magalhães, Valtair Severino Dos Santos Júnior, José Eduardo Goncalves, Renata Barbosa Oliveira, Vinicius Gonçalves Maltarollo, Rafael Wesley Bastos, Gustavo Goldman, Susana Johann, Nalu Teixeira de Aguiar Peres, Daniel de Assis Santos","doi":"10.1021/acsinfecdis.4c00732","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00732","url":null,"abstract":"Cryptococcosis is a severe fungal infection primarily caused by two encapsulated yeasts: Cryptococcus neoformans and C. gattii. The most significant complication is cryptococcal meningitis, where the fungus crosses the blood-brain barrier, leading to a severe brain infection. Current treatments, which include amphotericin B and flucytosine or fluconazole, are often toxic and not very effective. Therefore, there is a pressing need for new antifungal agents. This study screened 30 thiazole derivatives for their antifungal activity against Cryptococcus and their toxicity to brain cells. Four compounds (RN86, RN88, RJ37, and RVJ42) showed particularly strong effects. These compounds reduced ergosterol levels in the fungal membrane and inhibited its ability to cross the blood-brain barrier. Notably, RN86 and RVJ42 improved survival rates in a mouse model of cryptococcosis by lowering the fungal load in the lungs and brain. These findings suggest that these derivatives could be promising treatments for pulmonary and neurocryptococcosis.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363255","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

C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-06 DOI: 10.1021/acsinfecdis.4c00912

Emily E Williford, Yao-Peng Xue, Wai Kwan Tang, Ruihao Li, Katherine V Jones, Kevin S Blake, Helen C Blaine, Xiang Lian, Christina L Stallings, Niraj H Tolia, Gautam Dantas, Timothy A Wencewicz

{"title":"C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity.","authors":"Emily E Williford, Yao-Peng Xue, Wai Kwan Tang, Ruihao Li, Katherine V Jones, Kevin S Blake, Helen C Blaine, Xiang Lian, Christina L Stallings, Niraj H Tolia, Gautam Dantas, Timothy A Wencewicz","doi":"10.1021/acsinfecdis.4c00912","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00912","url":null,"abstract":"Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer-Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254157","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

Activity-Based Protein Profiling Identifies an α-Amylase Family Protein Contributing to the Virulence of Methicillin-Resistant Staphylococcus aureus.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-06 DOI: 10.1021/acsinfecdis.4c00638

Md Jalal Uddin, Kjersti Julin, Herman S Overkleeft, Mona Johannessen, Christian S Lentz

{"title":"Activity-Based Protein Profiling Identifies an α-Amylase Family Protein Contributing to the Virulence of Methicillin-Resistant Staphylococcus aureus.","authors":"Md Jalal Uddin, Kjersti Julin, Herman S Overkleeft, Mona Johannessen, Christian S Lentz","doi":"10.1021/acsinfecdis.4c00638","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00638","url":null,"abstract":"In search of new putative antimicrobial drug targets in methicillin-resistant Staphylococcus aureus, we aimed to identify and characterize retaining glycosidase activities in this bacterial pathogen. Using activity-based protein profiling (ABPP), a panel of 7 fluorescent probes was screened to detect activities of diverse retaining glycosidase families. Based on this, a cocktail of 3 biotinylated probes (targeting α-glucosidases, β-galactosidases and α-fucosidases) was used for target enrichment and three glycoside hydrolase family proteins were identified by mass-spectrometry: 6-phospho-β-glucosidase (BglA), α-amylase family protein trehalase C (TreC), and autolysin (Atl). The physiological relevance of previously uncharacterized BglA and TreC was addressed in CRISPRi and inhibitor studies with the putative TreC inhibitor α-cyclophellitol-aziridine. Silencing of treC did not affect bacterial growth in rich media, but reduced biofilm formation in vitro, and attenuated virulence during Galleria mellonella infection, warranting future investigations into the biochemical function of this enzyme.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363253","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

Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted M. tuberculosis Chorismate Mutase.

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-02-04 DOI: 10.1021/acsinfecdis.4c00798

Renier H P van Neer, Patricia K Dranchak, Mahesh Aitha, Lijun Liu, Emma K Carlson, Isabella E Jacobsen, Kevin Battaile, Yuhong Fang, Dingyin Tao, Ganesha Rai, Janak Padia, Scott Lovell, Hiroaki Suga, James Inglese

{"title":"Active- and Allosteric-Site Cyclic Peptide Inhibitors of Secreted M. tuberculosis Chorismate Mutase.","authors":"Renier H P van Neer, Patricia K Dranchak, Mahesh Aitha, Lijun Liu, Emma K Carlson, Isabella E Jacobsen, Kevin Battaile, Yuhong Fang, Dingyin Tao, Ganesha Rai, Janak Padia, Scott Lovell, Hiroaki Suga, James Inglese","doi":"10.1021/acsinfecdis.4c00798","DOIUrl":"10.1021/acsinfecdis.4c00798","url":null,"abstract":"The secreted Chorismate mutase enzyme of Mycobacterium tuberculosis (*MtbCM) is an underexplored potential target for the development of new antitubercular agents that are increasingly needed as antibiotic resistance rises in prevalence. As an enzyme suspected to be involved in virulence and host-pathogen interactions, disruption of its function could circumvent the difficulty of treating tuberculosis-infected granulomas. Drug development, however, is limited by novel ligand discovery. Currently, *MtbCM activity is measured by using a low throughput acid/base-mediated product derivatization absorbance assay. Here, we utilized an RNA-display affinity selection approach enabled by the Random Peptides Integrated Discovery (RaPID) system to screen a vast library of macrocyclic peptides (MCP) for novel *MtbCM ligands. Peptides identified from the RaPID selection, and analogs thereof identified by analyzing the selection population dynamics, produced a new class of *MtbCM inhibiting MCPs. Among these were two noteworthy \"chorismides\", whose binding modes were elucidated by X-ray crystallography. Both were potent inhibitors of the CM enzyme activity. One was identified as an allosteric binding peptide revealing a novel inhibition approach, while the other is an active-site binding peptide that when conjugated to a fluorescent probe allowed for the development of a series of alternative fluorescence-based ligand-displacement assays that can be utilized for the assessment of potential *MtbCM inhibitors.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187542","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