ACS Infectious Diseases最新文献_第2页

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13

Varsha Saini, Sayed M. Safwan, Devashish Mehta, Eric Evan Das and Avinash Bajaj*,

引用次数: 0

Unanticipated Lipid Redistribution Mechanism of Action by Conjugated Oligoelectrolyte Antibiotics. 偶联寡电解质抗生素作用的脂质再分配机制。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-03 DOI: 10.1021/acsinfecdis.4c00921

Samuel J W Chan, Jakkarin Limwongyut, Alex S Moreland, Ji-Yu Zhu, Kaixi Zhang, Guillermo C Bazan

{"title":"Unanticipated Lipid Redistribution Mechanism of Action by Conjugated Oligoelectrolyte Antibiotics.","authors":"Samuel J W Chan, Jakkarin Limwongyut, Alex S Moreland, Ji-Yu Zhu, Kaixi Zhang, Guillermo C Bazan","doi":"10.1021/acsinfecdis.4c00921","DOIUrl":"10.1021/acsinfecdis.4c00921","url":null,"abstract":"Antimicrobial resistance (AMR) is one of the most pressing global health threats, urgently requiring new classes of antibiotics with differentiated mechanisms of action (MOA). Conjugated oligoelectrolytes (COEs) represent a molecular platform for designing antimicrobial agents structurally distinct from commercially available drugs. However, questions remain regarding their MOA. Herein, we show that COE treatment causes distinct phenotypes from well-established membrane-active antibiotics, with differences arising from structural variations, such as pendant group hydrophobicity. This was revealed through bacterial cytological profiling approaches, single-cell quantitative morphological analysis, and dye localization following treatment against Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtilis) bacteria. E. coli treatment with PNH2 and 1B resulted in micrometer-sized membrane vesicles, which are absent in 2-2H-treated cells. COE-treated B. subtilis featured overproduction of regions of increased fluidity (RIFs), relative to untreated cells. In contrast to the originally postulated membrane pinching mechanism, these findings support a MOA for COEs that relies predominantly on membrane restructuring, thereby providing new guidelines for further COE-based antibiotic design.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1448-1459"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951867","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

Discovery of 2,4,5-Substituted Benzoxazole Derivatives as Pks13 Inhibitors via the Scaffold Hopping Strategy. 通过支架跳跃策略发现2,4,5-取代苯并恶唑衍生物作为Pks13抑制剂。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-08 DOI: 10.1021/acsinfecdis.4c01054

Babatunde Samuel Obadawo, Priscila Cristina Bartolomeu Halicki, Kindra L Becker, Jessica C Seeliger, Kyle H Rohde, Steven J Sucheck

{"title":"Discovery of 2,4,5-Substituted Benzoxazole Derivatives as Pks13 Inhibitors via the Scaffold Hopping Strategy.","authors":"Babatunde Samuel Obadawo, Priscila Cristina Bartolomeu Halicki, Kindra L Becker, Jessica C Seeliger, Kyle H Rohde, Steven J Sucheck","doi":"10.1021/acsinfecdis.4c01054","DOIUrl":"10.1021/acsinfecdis.4c01054","url":null,"abstract":"Pks13, an essential enzyme for Mycobacterium tuberculosis (Mtb) cell wall biosynthesis, represents a promising target for antimicrobial intervention. Previously, the benzofuran derivative TAM16 was identified as a potent inhibitor of Pks13 through interaction with the thioesterase (TE) domain, but its development was halted due to cardiotoxicity. Therefore, we sought to identify an alternative scaffold that demonstrated good whole-cell activity that we demonstrate had a mode of action (MOA) similar to that of TAM16. To achieve this, we employed a scaffold hopping approach, leading to the discovery of a benzoxazole (BZX) scaffold that was determined to target the Pks13 TE domain. We then explored various structure-activity relationship (SAR) studies of the series, which resulted in the identification of a prototype BZX lead. Several of the novel BZX compounds showed potent minimum inhibitory concentrations (MICs) against Mtb and low to no toxicity in cytotoxicity assays. These compounds showed on-target activity, as evidenced by the induction of the BCG iniBAC cell wall damage reporter, inhibition of mycolic acid synthesis, and resistance mutations mapping to the TE domain of Pks13 in Mycobacterium smegmatis (Msm). Overall, we believe that the BZX scaffold represents a new and promising structural class with high potential to advance antitubercular drug discovery.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1460-1472"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952497","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

Genome Mining and Chemistry-Driven Discovery of a Cell Wall Lipopeptide Signature for Mycobacterium avium subsp. paratuberculosis Ancestral Lineage. 禽分枝杆菌亚种细胞壁脂肽特征的基因组挖掘和化学驱动发现。副结核的祖先血统。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-05-21 DOI: 10.1021/acsinfecdis.5c00181

John P Bannantine, Gilles Etienne, Anne Lemassu, Thierry Cochard, Christelle Ganneau, Sandrine Melo, Cyril Conde, Hedia Marrakchi, Sylvie Bay, Franck Biet

{"title":"Genome Mining and Chemistry-Driven Discovery of a Cell Wall Lipopeptide Signature for Mycobacterium avium subsp. paratuberculosis Ancestral Lineage.","authors":"John P Bannantine, Gilles Etienne, Anne Lemassu, Thierry Cochard, Christelle Ganneau, Sandrine Melo, Cyril Conde, Hedia Marrakchi, Sylvie Bay, Franck Biet","doi":"10.1021/acsinfecdis.5c00181","DOIUrl":"10.1021/acsinfecdis.5c00181","url":null,"abstract":"Mycobacterium avium subsp. paratuberculosis (Map) causes Johne's disease (JD), a chronic infection responsible for considerable economic losses to dairy industries worldwide. Genetically clonal, Map has evolved into three distinct genetic lineages designated CII, for bovine strains, and SI and SIII, for ovine strains. Previous studies have established that Map does not produce glycopeptidolipids, characteristic of the cell wall surface of mycobacteria belonging to the M. avium complex, but rather sugar-free lipopeptide compounds synthesized by nonribosomal peptide synthetases. In this study, we combined genomic, machine learning, (bio)chemical, and analytical approaches to identify the metabolites biosynthesized by NRPS in the most ancestral SI strains of Map. We thus characterized a lipotripeptide (L3P-2) signature for the SI genetic lineage, demonstrating that the evolution of this Map subspecies has been accompanied by a diversification of the cell wall lipopeptides. Finally, L3P-2 shows promise for improved serological diagnosis of JD.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1635-1647"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118362","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

The Thienopyrimidinone Gamhépathiopine Targets the Q_O Site of Plasmodium falciparum Cytochrome b. 噻吩嘧啶甘胺嘧啶靶向恶性疟原虫细胞色素b的QO位点。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-06-03 DOI: 10.1021/acsinfecdis.5c00259

Natalie Wiedemar, Rachel Milne, Sandra Carvalho, Stephen Patterson, Mike Bodkin, Nicolas Masurier, Vincent Lisowski, Nicolas Primas, Pierre Verhaeghe, Graeme M Sloan, Susan Wyllie

{"title":"The Thienopyrimidinone Gamhépathiopine Targets the QO Site of Plasmodium falciparum Cytochrome b.","authors":"Natalie Wiedemar, Rachel Milne, Sandra Carvalho, Stephen Patterson, Mike Bodkin, Nicolas Masurier, Vincent Lisowski, Nicolas Primas, Pierre Verhaeghe, Graeme M Sloan, Susan Wyllie","doi":"10.1021/acsinfecdis.5c00259","DOIUrl":"10.1021/acsinfecdis.5c00259","url":null,"abstract":"Chemotherapy remains a key component of the arsenal of tools to fight malaria. Specifically, new drugs with diverse mechanism(s) of action are required to combat existing drug resistance. Here, we describe comprehensive studies to determine the molecular target(s) of gamhépathiopine, a thienopyrimidinone showing promise for the treatment of malaria. In vitro evolution of gamhépathiopine resistance and whole genome analyses identified mutations within the QO site of Plasmodium falciparum cytochrome b, part of complex III of the electron transport chain. Subsequent biochemical assays demonstrated that gamhépathiopine directly inhibits complex III activity. Furthermore, exogenous expression of Saccharomyces cerevisiae dihydroorotate dehydrogenase, known to render the electron transport chain dispensable in Plasmodium, results in complete abrogation of gamhépathiopine activity. Cross-resistance profiling and docking studies indicate that gamhépathiopine occupies a similar, but not identical, binding pose to the established QO-targeting antimalarial atovaquone. The implications of these findings for the future development of gamhépathiopine are discussed.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"1719-1728"},"PeriodicalIF":4.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214326","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 : 2025-06-13

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