ACS Infectious Diseases最新文献_第9页

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Jemma A. Montgomery, P. Holland Alday, Ryan Choi, Monique Khim, Bart L. Staker, Matthew A. Hulverson, Kayode K. Ojo, Erkang Fan, Wesley C. Van Voorhis and J. Stone Doggett*,

引用次数: 0

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Tian Li, Zhanhui Wang, Xiuying Zhang, Zhihui Hao, Yong Guo, Jianzhong Shen, Tony Velkov and Chongshan Dai*,

引用次数: 0

Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites. 具有抗多种顶复合体寄生虫活性的多功能咪唑支架。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-08 DOI: 10.1021/acsinfecdis.5c00049

Monique Khim, Jemma Montgomery, Mariana Laureano De Souza, Melvin Delvillar, Lyssa J Weible, Mayuri Prabakaran, Matthew A Hulverson, Tyler Eck, Rammohan Y Bheemanabonia, P Holland Alday, David P Rotella, J Stone Doggett, Bart L Staker, Kayode K Ojo, Purnima Bhanot

{"title":"Versatile Imidazole Scaffold with Potent Activity against Multiple Apicomplexan Parasites.","authors":"Monique Khim, Jemma Montgomery, Mariana Laureano De Souza, Melvin Delvillar, Lyssa J Weible, Mayuri Prabakaran, Matthew A Hulverson, Tyler Eck, Rammohan Y Bheemanabonia, P Holland Alday, David P Rotella, J Stone Doggett, Bart L Staker, Kayode K Ojo, Purnima Bhanot","doi":"10.1021/acsinfecdis.5c00049","DOIUrl":"10.1021/acsinfecdis.5c00049","url":null,"abstract":"Malaria, toxoplasmosis, and cryptosporidiosis are caused by apicomplexan parasites Plasmodium spp., Toxoplasma gondii, and Cryptosporidium parvum, respectively, and pose major health challenges. Their therapies are inadequate, ineffective or threatened by drug resistance. The development of novel drugs against them requires innovative and resource-efficient strategies. We exploited the kinome conservation of these parasites to determine the cellular targets and effects of two Plasmodium falciparum inhibitors in T. gondii and C. parvum. The imidazoles, (R)-RY-1-165 and (R)-RY-1-185, were developed to target the cGMP dependent protein kinase of P. falciparum (PfPKG), orthologs of which are present in T. gondii and C. parvum. Using structural and modeling approaches we determined that the molecules bind stereospecifically and interact with PfPKG in a manner unique among described inhibitors. We used enzymatic assays and mutant P. falciparum expressing PfPKG with a substituted \"gatekeeper\" residue to determine that cellular activity of the molecules is mediated through targets additional to PfPKG. These likely include P. falciparum calcium dependent protein kinase 1 and 4 (PfCDPK-1, -4), kinases that, like PfPKG, have small amino acids at the \"gatekeeper\" position. The molecules are active against T. gondii and C. parvum, with T. gondii tachyzoites being particularly sensitive. Using mutant parasites, enzyme assays and modeling studies we demonstrate that targets in T. gondii include TgPKG, TgCDPK1, TgCDPK4 and the mitogen activated kinase-like 1 (MAPKL-1). Our results suggest that this scaffold holds promise for the development of new toxoplasmosis drugs.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1497-1507"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951446","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

Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease. P2基团的空间和电子性质对共价抑制剂与SARS-CoV-2主蛋白酶结合的影响。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-29 DOI: 10.1021/acsinfecdis.5c00246

Dipendra Bhandari, Leighton Coates, Annie Aniana, John M Louis, Peter V Bonnesen, Andrey Kovalevsky

{"title":"Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease.","authors":"Dipendra Bhandari, Leighton Coates, Annie Aniana, John M Louis, Peter V Bonnesen, Andrey Kovalevsky","doi":"10.1021/acsinfecdis.5c00246","DOIUrl":"10.1021/acsinfecdis.5c00246","url":null,"abstract":"The main protease (MPro) of SARS-CoV-2 is a critical enzyme required for viral replication, making it a prime target for antiviral drug development. Covalent inhibitors, which form a stable interaction with the catalytic C145, have demonstrated strong inhibition of MPro, but the influence of steric and electronic properties of P2 substituents, designed to engage the S2 substrate-binding subsite within the MPro active site, on inhibitor binding affinity remains underexplored. In this study, we design and characterize two hybrid covalent inhibitors, BBH-3 and BBH-4, and present their X-ray crystallographic structures in complex with MPro, providing molecular insights into how their distinct P2 groups, a dichlorobenzyl moiety in BBH-3 and an adamantyl substituent in BBH-4, affect binding conformation and active site adaptability. Comparative structural analyses with previously characterized inhibitors, including BBH-2 and Mcule-5948770040, reveal how the P2 bulkiness and electronic properties influence active site dynamics, particularly through interactions with the S2 and S5 subsites. The P2 group of BBH-3 induces conformational shifts in the S2 helix and the S5 loop, while BBH-4 displaces M49, stabilizing its binding through hydrophobic interactions. Isothermal titration calorimetry further elucidates the impact of P2 modifications on inhibitor affinity, revealing a delicate balance between enthalpic and entropic contributions. The data demonstrate that BBH-3 exhibits less favorable binding, affirming that dichlorobenzyl substitution at the P2 position has a more negative impact on the affinity for MPro than bulky saturated cyclic groups. This underscores the feature that MPro active site malleability may be accompanied by a conformational strain.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1697-1706"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172076","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

Antimicrobial Activity of Brilacidin against E. coli. 砖酸素对大肠杆菌的抑菌活性研究。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-06-03 DOI: 10.1021/acsinfecdis.5c00023

Michael J Wilhelm, Mohammad Sharifian Gh, Bruk Mensa, Gabriella L Howell, William F DeGrado, Hai-Lung Dai

{"title":"Antimicrobial Activity of Brilacidin against E. coli.","authors":"Michael J Wilhelm, Mohammad Sharifian Gh, Bruk Mensa, Gabriella L Howell, William F DeGrado, Hai-Lung Dai","doi":"10.1021/acsinfecdis.5c00023","DOIUrl":"10.1021/acsinfecdis.5c00023","url":null,"abstract":"Brilacidin (BRI) is a potent small-molecule mimic of antimicrobial peptides that has demonstrated efficacy against various pathogens. To better understand its antimicrobial mechanism of action, we investigated the interactions of BRI with the membranes of Escherichia coli. Specifically, the surface-sensitive nonlinear optical technique, second harmonic laser scattering (SHS), was used to monitor BRI-induced changes in the permeabilities of the dual phospholipid membranes of E. coli by measuring the adsorption and transport of a membrane-permeable indicator molecule (the quaternary ammonium cation, malachite green). Following exposure to 0.6 to 12× MIC BRI, the permeability of the outer membrane was shown to increase 2-fold. Conversely, the permeability of the inner membrane was shown to exhibit more complicated behavior: Permeability increased for near-MIC doses (≤3× MIC) of BRI but was significantly reduced for higher concentrations. The latter is consistent with the depolarization of the inner membrane, which was previously predicted in a computational study. The interpretation of the SHS results was corroborated with complementary assays that measure the permeability of small polar molecules to periplasmic versus cytosolic enzymes, as well as ATP luminescence and Western blot assays (for accumulation of secreted protein precursors). It is suggested that the mechanism of action of BRI against E. coli consists of a sequential and complementary attack on both membranes, beginning with an immediate and persistent increase in the permeability of the outer membrane and followed by likely depolarization of the inner membrane. This study also illustrates a new quantitative capability for monitoring antimicrobial interactions by using time-resolved SHS.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1486-1496"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207125","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

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Anne E. Mattingly, Haoting Li, Roberta J. Melander and Christian Melander*,

引用次数: 0

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Yuehong Chen, Wenguang Yang, Liangning Liao, Jing Li, Sen Zhang, Xiaoping Kang, Yuchang Li, Lu Zhao, Bao Dong, Huiyao Wang, Yi Hu*, Ye Feng* and Tao Jiang*,

引用次数: 0

Galectins as Drivers of Host-Pathogen Dynamics in Mycobacterium tuberculosis Infection. 半凝集素作为结核分枝杆菌感染宿主-病原体动力学的驱动因子。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-09 DOI: 10.1021/acsinfecdis.4c01056

Anjali Gangwar, Sapna Saini, Rashmi Sharma

{"title":"Galectins as Drivers of Host-Pathogen Dynamics in Mycobacterium tuberculosis Infection.","authors":"Anjali Gangwar, Sapna Saini, Rashmi Sharma","doi":"10.1021/acsinfecdis.4c01056","DOIUrl":"10.1021/acsinfecdis.4c01056","url":null,"abstract":"Galectins form a protein family with a conserved carbohydrate-binding domain that specifically interacts with β-galactoside-containing glycoconjugates, which are found abundantly on mammalian cell surfaces. These proteins play crucial roles in various physiological and pathological processes including immune responses, cell adhesion, inflammation, and apoptosis. During tuberculosis infection, galectins exert diverse impacts on pathogenesis. The interaction between host and pathogen during TB involves intricate mechanisms influencing disease outcomes, where the pathogen exploits host glycosylation patterns to evade immune detection, underscoring the significant role of galectins in regulating these crucial host-pathogen interactions. Galectins facilitate pathogen recognition, enhance the phagocytosis of mycobacteria, support the formation of granuloma, and carefully balance the protective immunity against potential tissue damage. Additionally, galectins have an impact on the cytokine milieu by regulating the levels of pro-inflammatory cytokines and chemokines, essential for orchestrating granuloma formation and maintaining tuberculosis-associated homeostasis. This review delves into the intricate connection between galectins and tuberculosis; uncovering essential molecular mechanisms that deepen our understanding of how these proteins contribute to combating this pervasive infectious disease. Here we discuss the multifaceted roles that galectins play to uniquely and critically influence the core dynamics of host-pathogen interactions in tuberculosis.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1347-1365"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953771","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

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Timothy J. Kotzé, Konrad J. Mostert, Riyad Domingo, Xu Wang, Wessel J. A. Moolman, Hailey S. Butman, Abigail Pepin, Kyle T. McKay, Deon P. Neveling, Joanna C. Evans, Valerie Mizrahi, Willem A. L. van Otterlo, Cynthia S. Dowd* and Erick Strauss*,

引用次数: 0

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Dipendra Bhandari, Leighton Coates, Annie Aniana, John M. Louis, Peter V. Bonnesen* and Andrey Kovalevsky*,

引用次数: 0