ACS Infectious Diseases最新文献_第9页

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents. 利用环胍的氨基二氢三嗪基团鉴定创新型叶酸抑制剂作为抗布氏锥虫药物的潜力。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-02 DOI: 10.1021/acsinfecdis.4c00113

Valeria Francesconi, Marco Rizzo, Cecilia Pozzi, Lorenzo Tagliazucchi, Claude U Konchie Simo, Giulia Saporito, Giacomo Landi, Stefano Mangani, Anna Carbone, Silvia Schenone, Nuno Santarém, Joana Tavares, Anabela Cordeiro-da-Silva, Maria Paola Costi, Michele Tonelli

{"title":"Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents.","authors":"Valeria Francesconi, Marco Rizzo, Cecilia Pozzi, Lorenzo Tagliazucchi, Claude U Konchie Simo, Giulia Saporito, Giacomo Landi, Stefano Mangani, Anna Carbone, Silvia Schenone, Nuno Santarém, Joana Tavares, Anabela Cordeiro-da-Silva, Maria Paola Costi, Michele Tonelli","doi":"10.1021/acsinfecdis.4c00113","DOIUrl":"10.1021/acsinfecdis.4c00113","url":null,"abstract":"Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (Ki = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489865","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

Inhibitors of the Structural and Nonstructural Proteins of Alphaviruses. 阿尔法病毒结构蛋白和非结构蛋白的抑制剂。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-11 DOI: 10.1021/acsinfecdis.4c00254

Damilohun Samuel Metibemu, Olawale Samuel Adeyinka, John Falode, Olamide Crown, Ifedayo Victor Ogungbe

引用次数: 0

A Micronemal Protein, Scot1, Is Essential for Apicoplast Biogenesis and Liver Stage Development in Plasmodium berghei. 贝氏疟原虫的一种微粒体蛋白--Scot1--是外生殖器生物发生和肝脏阶段发育所必需的

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-22 DOI: 10.1021/acsinfecdis.4c00362

Ankit Ghosh, Akancha Mishra, Raksha Devi, Sunil Kumar Narwal, Nirdosh, Pratik Narain Srivastava, Satish Mishra

{"title":"A Micronemal Protein, Scot1, Is Essential for Apicoplast Biogenesis and Liver Stage Development in Plasmodium berghei.","authors":"Ankit Ghosh, Akancha Mishra, Raksha Devi, Sunil Kumar Narwal, Nirdosh, Pratik Narain Srivastava, Satish Mishra","doi":"10.1021/acsinfecdis.4c00362","DOIUrl":"10.1021/acsinfecdis.4c00362","url":null,"abstract":"Plasmodium sporozoites invade hepatocytes, transform into liver stages, and replicate into thousands of merozoites that infect erythrocytes and cause malaria. Proteins secreted from micronemes play an essential role in hepatocyte invasion, and unneeded micronemes are subsequently discarded for replication. The liver-stage parasites are potent immunogens that prevent malarial infection. Late liver stage-arresting genetically attenuated parasites (GAPs) exhibit greater protective efficacy than early GAP. However, the number of late liver-stage GAPs for generating GAPs with multiple gene deletions is limited. Here, we identified Scot1 (Sporozoite Conserved Orthologous Transcript 1), which was previously shown to be upregulated in sporozoites, and by endogenous tagging with mCherry, we demonstrated that it is expressed in the sporozoite and liver stages in micronemes. Using targeted gene deletion in Plasmodium berghei, we showed that Scot1 is essential for late liver-stage development. Scot1 KO sporozoites grew normally into liver stages but failed to initiate blood-stage infection in mice due to impaired apicoplast biogenesis and merozoite formation. Bioinformatic studies suggested that Scot1 is a metal-small-molecule carrier protein. Remarkably, supplementation with metals in the culture of infected Scot1 KO cells did not rescue their phenotype. Immunization with Scot1 KO sporozoites in C57BL/6 mice confers protection against malaria via infection. These proof-of-concept studies will enable the generation of P. falciparum Scot1 mutants that could be exploited to generate GAP malaria vaccines.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732767","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 ER-Resident Ras Inhibitor 1 (Eri1) of Candida albicans Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway. 白色念珠菌的 ER 驻留 Ras 抑制剂 1 (Eri1) 通过 Ras 依赖性 cAMP-PKA 通路抑制菌丝发生。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 DOI: 10.1021/acsinfecdis.4c00175

Subhash Chandra Sethi, Monika Bharati, Yatin Kumar, Usha Yadav, Harshita Saini, Parvez Alam, Sneha Sudha Komath

{"title":"The ER-Resident Ras Inhibitor 1 (Eri1) of Candida albicans Inhibits Hyphal Morphogenesis via the Ras-Independent cAMP-PKA Pathway.","authors":"Subhash Chandra Sethi, Monika Bharati, Yatin Kumar, Usha Yadav, Harshita Saini, Parvez Alam, Sneha Sudha Komath","doi":"10.1021/acsinfecdis.4c00175","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00175","url":null,"abstract":"Ras signaling and glycosylphosphatidylinositol (GPI) biosynthesis are mutually inhibitory in S. cerevisiae (Sc). The inhibition is mediated via an interaction of yeast Ras2 with the Eri1 subunit of its GPI-N-acetylglucosaminyl transferase (GPI-GnT), the enzyme catalyzing the very first GPI biosynthetic step. In contrast, Ras signaling and GPI biosynthesis in C. albicans (Ca) are mutually activated and together control the virulence traits of the human fungal pathogen. What might be the role of Eri1 in this pathogen? The present manuscript addresses this question while simultaneously characterizing the cellular role of CaEri1. It is either nonessential or required at very low levels for cell viability in C. albicans. Severe depletion of CaEri1 results in reduced GPI biosynthesis and cell wall defects. It also produces hyperfilamentation phenotypes in Spider medium as well as in bicarbonate medium containing 5% CO2, suggesting that both the Ras-dependent and Ras-independent cAMP-PKA pathways for hyphal morphogenesis are activated in these cells. Pull-down and acceptor-photobleaching FRET experiments suggest that CaEri1 does not directly interact with CaRas1 but does so through CaGpi2, another GPI-GnT subunit. We showed previously that CaGpi2 is downstream of CaEri1 in cross talk with CaRas1 and for Ras-dependent hyphal morphogenesis. Here we show that CaEri1 is downstream of all GPI-GnT subunits in inhibiting Ras-independent filamentation. CaERI1 also participates in intersubunit transcriptional cross talk within the GPI-GnT, a feature unique to C. albicans. Virulence studies using G. mellonella larvae show that a heterozygous strain of CaERI1 is better cleared by the host and is attenuated in virulence.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904954","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

Targeting Leishmania Promastigotes and Amastigotes Forms through Amino Acids and Peptides: A Promising Therapeutic Strategy. 通过氨基酸和肽靶向利什曼原虫和非原虫：一种前景广阔的治疗策略。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-01 DOI: 10.1021/acsinfecdis.4c00089

Charmante Registre, Luciana Miranda Silva, Farah Registre, Rodrigo Dian de Oliveira Aguiar Soares, Karina Taciana Santos Rubio, Simone Pinto Carneiro, Orlando David Henrique Dos Santos

引用次数: 0

Conserved Evolutionary Trajectory Can Be Perturbed to Prevent Resistance Evolution under Norfloxacin Pressure by Forcing Mycobacterium smegmatis on Alternate Evolutionary Paths. 在诺氟沙星的压力下，可以扰乱保守的进化轨迹，通过迫使分枝杆菌走上替代性进化路径来防止耐药性进化。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-03 DOI: 10.1021/acsinfecdis.3c00605

Akanksha, Sarika Mehra

{"title":"Conserved Evolutionary Trajectory Can Be Perturbed to Prevent Resistance Evolution under Norfloxacin Pressure by Forcing Mycobacterium smegmatis on Alternate Evolutionary Paths.","authors":"Akanksha, Sarika Mehra","doi":"10.1021/acsinfecdis.3c00605","DOIUrl":"10.1021/acsinfecdis.3c00605","url":null,"abstract":"Antibiotic resistance is a pressing health issue, with the emergence of resistance in bacteria outcompeting the discovery of novel drug candidates. While many studies have used Adaptive Laboratory Evolution (ALE) to understand the determinants of resistance, the influence of the drug dosing profile on the evolutionary trajectory remains understudied. In this study, we employed ALE on Mycobacterium smegmatis exposed to various concentrations of Norfloxacin using both cyclic constant and stepwise increasing drug dosages to examine their impact on the resistance mechanisms selected. Mutations in an efflux pump regulator, LfrR, were found in all of the evolved populations irrespective of the drug profile and population bottleneck, indicating a conserved efflux-based resistance mechanism. This mutation appeared early in the evolutionary trajectory, providing low-level resistance when present alone, with a further increase in resistance resulting from successive accumulation of other mutations. Notably, drug target mutations, similar to those observed in clinical isolates, were only seen above a threshold of greater than 4× the minimum inhibitory concentration (MIC). A combination of three mutations in the genes, lfrR, MSMEG_1959, and MSMEG_5045, was conserved across multiple lineages, leading to high-level resistance and preceding the appearance of drug target mutations. Interestingly, in populations evolved from parental strains lacking the lfrA efflux pump, the primary target of the lfrR regulator, no lfrR gene mutations are selected. Furthermore, evolutional trajectories originating from the ΔlfrA strain displayed early arrest in some lineages and the absence of target gene mutations in those that evolved, albeit delayed. Thus, blocking or inhibiting the expression of efflux pumps can arrest or delay the fixation of drug target mutations, potentially limiting the maximum attainable resistance levels.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496295","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

Antifungal Tetrahydrocarbazole Compound CAR-8 Induces Endoplasmic Reticulum Stress in Candida albicans. 抗真菌四氢咔唑化合物 CAR-8 诱导白色念珠菌的内质网应激

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-11 DOI: 10.1021/acsinfecdis.4c00069

Wen Chao, Lijuan Qiu, Lu Gao, Jia Feng, Yu Liu, Lan Yan, Yuanying Jiang, Quanzhen Lv

{"title":"Antifungal Tetrahydrocarbazole Compound CAR-8 Induces Endoplasmic Reticulum Stress in Candida albicans.","authors":"Wen Chao, Lijuan Qiu, Lu Gao, Jia Feng, Yu Liu, Lan Yan, Yuanying Jiang, Quanzhen Lv","doi":"10.1021/acsinfecdis.4c00069","DOIUrl":"10.1021/acsinfecdis.4c00069","url":null,"abstract":"The development of new effective antifungal agents is essential to combat fungal infections. Tetrahydrocarbazole has been exploited as a promising skeleton against various pathogenic microorganisms and is used to search for novel active antifungal compounds. In this study, a library composed of small tetrahydrocarbazole compounds was screened, and a potent antifungal agent, CAR-8, was identified with a minimum inhibitory concentration of 2-4 μg/mL against Candida albicans. CAR-8 showed strong fungicidal activities and killed almost all C. albicans within 3 h at a concentration of 16 μg/mL. At concentrations of 2 and 8 μg/mL, CAR-8 significantly inhibited the formation of hyphae and biofilms. Moreover, CAR-8 at 10 and 20 mg/kg reduced the fungal load and improved the survival in the C. albicans infection model in the invertebrate Galleria mellonella. Transcriptome analysis revealed significant changes in the expression of genes associated with protein processing in the endoplasmic reticulum (ER), ER-associated degradation, and unfolded protein response (UPR), which suggested that CAR-8 treatment induced ER stress. Moreover, CAR-8 treatment resulted in various phenotypes similar to tunicamycin, a classical ER stress inducer. These included nonconventional splicing of HAC1 mRNA, the fragmented morphology of ER, the distribution changes of GFP-Snc1 in Saccharomyces cerevisiae, and cell apoptosis probably caused by ER stress. More importantly, the disruption of IRE1 or HAC1 increased the sensitivity of C. albicans to CAR-8, confirming that the UPR signaling pathway was critical for CAR-8 resistance. Overall, our study identifies a potent ER stress-induced antifungal compound that will help the discovery of new antifungal drugs.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578192","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

Acknowledgment of "Star Reviewers" over the Past Decade for ACS Infectious Diseases. 感谢过去十年 ACS 传染病杂志的 "明星审稿人"。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-07-31 DOI: 10.1021/acsinfecdis.4c00584

Jayanta Haldar

引用次数: 0

Uncovering Endolysins against Methicillin-Resistant Staphylococcus aureus Using a Microbial Single-Cell Genome Database. 利用微生物单细胞基因组数据库发现抗耐甲氧西林金黄色葡萄球菌的内溶酶。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-06-21 DOI: 10.1021/acsinfecdis.4c00039

Takuya Yoda, Ayumi Matsuhashi, Ai Matsushita, Shohei Shibagaki, Yukie Sasakura, Kazuteru Aoki, Masahito Hosokawa, Soichiro Tsuda

{"title":"Uncovering Endolysins against Methicillin-Resistant Staphylococcus aureus Using a Microbial Single-Cell Genome Database.","authors":"Takuya Yoda, Ayumi Matsuhashi, Ai Matsushita, Shohei Shibagaki, Yukie Sasakura, Kazuteru Aoki, Masahito Hosokawa, Soichiro Tsuda","doi":"10.1021/acsinfecdis.4c00039","DOIUrl":"10.1021/acsinfecdis.4c00039","url":null,"abstract":"Endolysins, peptidoglycan hydrolases derived from bacteriophages (phages), are being developed as a promising alternative to conventional antibiotics. To obtain highly active endolysins, a diverse library of these endolysins is vital. We propose here microbial single-cell genome sequencing as an efficient tool to discover dozens of previously unknown endolysins, owing to its culture-independent sequencing method. As a proof of concept, we analyzed and recovered endolysin genes within prophage regions of Staphylococcus single-amplified genomes in human skin microbiome samples. We constructed a library of chimeric endolysins by shuffling domains of the natural endolysins and performed high-throughput screening against Staphylococcus aureus. One of the lead endolysins, bbst1027, exhibited desirable antimicrobial properties, such as rapid bactericidal activity, no detectable resistance development, and in vivo efficacy. We foresee that this endolysin discovery pipeline is in principle applicable to any bacterial target and boost the development of novel antimicrobial agents.","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436382","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

Decoding Bacterial Persistence: Mechanisms and Strategies for Effective Eradication. 解码细菌的持久性：有效根除细菌的机制和策略》。

IF 4 2区医学

ACS Infectious Diseases Pub Date : 2024-08-09 Epub Date: 2024-06-28 DOI: 10.1021/acsinfecdis.4c00270

Abhiroop Sett, Vineet Dubey, Somok Bhowmik, Ranjana Pathania

引用次数: 0