Pub Date : 2024-05-07DOI: 10.1021/acsinfecdis.4c00133
Sasya Madhurantakam, Jayanth Babu Karnam, Vikram Narayanan Dhamu, Santosh Seetaraman, Marcellene A. Gates-Hollingsworth, David P. AuCoin, Danielle V. Clark, Kevin L. Schully, Sriram Muthukumar* and Shalini Prasad*,
This study presented the detection and quantification of capsular polysaccharide (CPS) as a biomarker for the diagnosis of melioidosis. After successfully screening four monoclonal antibodies (mAbs) previously determined to bind CPS molecules, the team developed a portable electrochemical immunosensor based on antibody–antigen interactions. The biosensor was able to detect CPS with a wide detection range from 0.1pg/mL to 1 μg/mL. The developed biosensor achieved high sensitivity for the detection of CPS spiked into both urine and serum. The developed assay platform was successfully programmed into a Windows app, and the sensor performance was evaluated with different spiked concentrations. The rapid electro-analytical device (READ) sensor showed great unprecedented sensitivity for the detection of CPS molecules in both serum and urine, and results were cross-validated with ELISA methods.
{"title":"Electrochemical Immunoassay for Capturing Capsular Polysaccharide of Burkholderia pseudomallei: Early Onsite Detection of Melioidosis","authors":"Sasya Madhurantakam, Jayanth Babu Karnam, Vikram Narayanan Dhamu, Santosh Seetaraman, Marcellene A. Gates-Hollingsworth, David P. AuCoin, Danielle V. Clark, Kevin L. Schully, Sriram Muthukumar* and Shalini Prasad*, ","doi":"10.1021/acsinfecdis.4c00133","DOIUrl":"10.1021/acsinfecdis.4c00133","url":null,"abstract":"<p >This study presented the detection and quantification of capsular polysaccharide (CPS) as a biomarker for the diagnosis of melioidosis. After successfully screening four monoclonal antibodies (mAbs) previously determined to bind CPS molecules, the team developed a portable electrochemical immunosensor based on antibody–antigen interactions. The biosensor was able to detect CPS with a wide detection range from 0.1pg/mL to 1 μg/mL. The developed biosensor achieved high sensitivity for the detection of CPS spiked into both urine and serum. The developed assay platform was successfully programmed into a Windows app, and the sensor performance was evaluated with different spiked concentrations. The rapid electro-analytical device (READ) sensor showed great unprecedented sensitivity for the detection of CPS molecules in both serum and urine, and results were cross-validated with ELISA methods.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846612","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}
Pub Date : 2024-05-04DOI: 10.1021/acsinfecdis.3c00718
Ke Li, Chao Lin, Yu-Han Hu, Jun Wang, Zhen Jin, Zhen-Ling Zeng* and You-Zhi Tang*,
In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 μg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 μg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (−1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (−1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 μg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of −9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.
{"title":"Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole","authors":"Ke Li, Chao Lin, Yu-Han Hu, Jun Wang, Zhen Jin, Zhen-Ling Zeng* and You-Zhi Tang*, ","doi":"10.1021/acsinfecdis.3c00718","DOIUrl":"10.1021/acsinfecdis.3c00718","url":null,"abstract":"<p >In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The <i>in vitro</i> antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 μg/mL), compound <b>14</b> exhibited potency in inhibiting MRSA growth (MIC = 0.0625 μg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound <b>14</b> could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound <b>14</b> was 1.29 h. Additionally, in thigh-infected mice, compound <b>14</b> exhibited a more potent antibacterial efficacy (−1.78 ± 0.28 log<sub>10</sub> CFU/g) in reducing MRSA load compared to tiamulin (−1.21 ± 0.23 log<sub>10</sub> CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound <b>14</b> (8 μg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound <b>14</b> toward the 50S ribosomal subunit, with a binding free energy of −9.63 kcal/mol. Taken together, it could be deduced that compound <b>14</b> was a promising candidate for treating MRSA infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841439","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}
Pub Date : 2024-05-02DOI: 10.1021/acsinfecdis.4c00157
Joshua M. E. Adams, Peri B. Moulding and Omar M. El-Halfawy*,
Chemicals bacteria encounter at the infection site could shape their stress and antibiotic responses; such effects are typically undetected under standard lab conditions. Polyamines are small molecules typically overproduced by the host during infection and have been shown to alter bacterial stress responses. We sought to determine the effect of polyamines on the antibiotic response of Klebsiella pneumoniae, a Gram-negative priority pathogen. Interestingly, putrescine and other natural polyamines sensitized K. pneumoniae to azithromycin, a macrolide protein translation inhibitor typically used for Gram-positive bacteria. This synergy was further potentiated in the physiological buffer, bicarbonate. Chemical genomic screens suggested a dual mechanism, whereby putrescine acts at the membrane and ribosome levels. Putrescine permeabilized the outer membrane of K. pneumoniae (NPN and β-lactamase assays) and the inner membrane (Escherichia coli β-galactosidase assays). Chemically and genetically perturbing membranes led to a loss of putrescine–azithromycin synergy. Putrescine also inhibited protein synthesis in an E. coli-derived cell-free protein expression assay simultaneously monitoring transcription and translation. Profiling the putrescine–azithromycin synergy against a combinatorial array of antibiotics targeting various ribosomal sites suggested that putrescine acts as tetracyclines targeting the 30S ribosomal acceptor site. Next, exploiting the natural polyamine–azithromycin synergy, we screened a polyamine analogue library for azithromycin adjuvants, discovering four azithromycin synergists with activity starting from the low micromolar range and mechanisms similar to putrescine. This work sheds light on the bacterial antibiotic responses under conditions more reflective of those at the infection site and provides a new strategy to extend the macrolide spectrum to drug-resistant K. pneumoniae.
{"title":"Polyamine-Mediated Sensitization of Klebsiella pneumoniae to Macrolides through a Dual Mode of Action","authors":"Joshua M. E. Adams, Peri B. Moulding and Omar M. El-Halfawy*, ","doi":"10.1021/acsinfecdis.4c00157","DOIUrl":"10.1021/acsinfecdis.4c00157","url":null,"abstract":"<p >Chemicals bacteria encounter at the infection site could shape their stress and antibiotic responses; such effects are typically undetected under standard lab conditions. Polyamines are small molecules typically overproduced by the host during infection and have been shown to alter bacterial stress responses. We sought to determine the effect of polyamines on the antibiotic response of <i>Klebsiella pneumoniae</i>, a Gram-negative priority pathogen. Interestingly, putrescine and other natural polyamines sensitized <i>K. pneumoniae</i> to azithromycin, a macrolide protein translation inhibitor typically used for Gram-positive bacteria. This synergy was further potentiated in the physiological buffer, bicarbonate. Chemical genomic screens suggested a dual mechanism, whereby putrescine acts at the membrane and ribosome levels. Putrescine permeabilized the outer membrane of <i>K. pneumoniae</i> (NPN and β-lactamase assays) and the inner membrane (<i>Escherichia coli</i> β-galactosidase assays). Chemically and genetically perturbing membranes led to a loss of putrescine–azithromycin synergy. Putrescine also inhibited protein synthesis in an <i>E. coli</i>-derived cell-free protein expression assay simultaneously monitoring transcription and translation. Profiling the putrescine–azithromycin synergy against a combinatorial array of antibiotics targeting various ribosomal sites suggested that putrescine acts as tetracyclines targeting the 30S ribosomal acceptor site. Next, exploiting the natural polyamine–azithromycin synergy, we screened a polyamine analogue library for azithromycin adjuvants, discovering four azithromycin synergists with activity starting from the low micromolar range and mechanisms similar to putrescine. This work sheds light on the bacterial antibiotic responses under conditions more reflective of those at the infection site and provides a new strategy to extend the macrolide spectrum to drug-resistant <i>K. pneumoniae</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841545","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}
Pub Date : 2024-05-01DOI: 10.1021/acsinfecdis.4c00115
Krittika Ralhan, Kavita A. Iyer, Leilani Lotti Diaz, Robert Bird, Ankush Maind and Qiongqiong Angela Zhou*,
The development of effective antibacterial solutions has become paramount in maintaining global health in this era of increasing bacterial threats and rampant antibiotic resistance. Traditional antibiotics have played a significant role in combating bacterial infections throughout history. However, the emergence of novel resistant strains necessitates constant innovation in antibacterial research. We have analyzed the data on antibacterials from the CAS Content Collection, the largest human-curated collection of published scientific knowledge, which has proven valuable for quantitative analysis of global scientific knowledge. Our analysis focuses on mining the CAS Content Collection data for recent publications (since 2012). This article aims to explore the intricate landscape of antibacterial research while reviewing the advancement from traditional antibiotics to novel and emerging antibacterial strategies. By delving into the resistance mechanisms, this paper highlights the need to find alternate strategies to address the growing concern.
{"title":"Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies","authors":"Krittika Ralhan, Kavita A. Iyer, Leilani Lotti Diaz, Robert Bird, Ankush Maind and Qiongqiong Angela Zhou*, ","doi":"10.1021/acsinfecdis.4c00115","DOIUrl":"10.1021/acsinfecdis.4c00115","url":null,"abstract":"<p >The development of effective antibacterial solutions has become paramount in maintaining global health in this era of increasing bacterial threats and rampant antibiotic resistance. Traditional antibiotics have played a significant role in combating bacterial infections throughout history. However, the emergence of novel resistant strains necessitates constant innovation in antibacterial research. We have analyzed the data on antibacterials from the CAS Content Collection, the largest human-curated collection of published scientific knowledge, which has proven valuable for quantitative analysis of global scientific knowledge. Our analysis focuses on mining the CAS Content Collection data for recent publications (since 2012). This article aims to explore the intricate landscape of antibacterial research while reviewing the advancement from traditional antibiotics to novel and emerging antibacterial strategies. By delving into the resistance mechanisms, this paper highlights the need to find alternate strategies to address the growing concern.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841622","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}
Pub Date : 2024-04-30DOI: 10.1021/acsinfecdis.4c00020
Natalie Fuchs, Robert A. Zimmermann, Marvin Schwickert, Annika Gunkel, Collin Zimmer, Mergim Meta, Kevin Schwickert, Jennifer Keiser, Cécile Haeberli, Werner Kiefer and Tanja Schirmeister*,
In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm Schistosoma mansoni and its target protease S. mansoni cathepsin B1 (SmCB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds’ in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in S. mansoni newly transformed schistosomula (NTS), adult worms, and SmCB1 inhibition. The optimized compounds from both approaches (“phenotypic” vs “SmCB1” approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the “SmCB1” approach emerging as the most potent compound. 2h displayed nanomolar inhibition of SmCB1 (Ki = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound 2h toward S. mansoni adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.
{"title":"Dual Strategy to Design New Agents Targeting Schistosoma mansoni: Advancing Phenotypic and SmCB1 Inhibitors for Improved Efficacy","authors":"Natalie Fuchs, Robert A. Zimmermann, Marvin Schwickert, Annika Gunkel, Collin Zimmer, Mergim Meta, Kevin Schwickert, Jennifer Keiser, Cécile Haeberli, Werner Kiefer and Tanja Schirmeister*, ","doi":"10.1021/acsinfecdis.4c00020","DOIUrl":"10.1021/acsinfecdis.4c00020","url":null,"abstract":"<p >In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm <i>Schistosoma mansoni</i> and its target protease <i>S. mansoni</i> cathepsin B1 (<i>Sm</i>CB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds’ in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in <i>S. mansoni</i> newly transformed schistosomula (NTS), adult worms, and <i>Sm</i>CB1 inhibition. The optimized compounds from both approaches (“phenotypic” vs “<i>Sm</i>CB1” approach) demonstrated improved efficacy against <i>S. mansoni</i> NTS and adult worms, with <b>2h</b> from the “<i>Sm</i>CB1” approach emerging as the most potent compound. <b>2h</b> displayed nanomolar inhibition of <i>Sm</i>CB1 (<i>K</i><sub>i</sub> = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound <b>2h</b> toward <i>S. mansoni</i> adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841698","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}
Pub Date : 2024-04-29DOI: 10.1021/acsinfecdis.4c00082
Mansi Tanwar, Anamika Singh, Tej Pal Singh, Sujata Sharma* and Pradeep Sharma*,
Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood–brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.
{"title":"Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis","authors":"Mansi Tanwar, Anamika Singh, Tej Pal Singh, Sujata Sharma* and Pradeep Sharma*, ","doi":"10.1021/acsinfecdis.4c00082","DOIUrl":"10.1021/acsinfecdis.4c00082","url":null,"abstract":"<p >Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood–brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811697","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}
Pub Date : 2024-04-29DOI: 10.1021/acsinfecdis.3c00622
Alisa Vaknin, Alon Grossman, Natasha D. Durham, Inbal Lupovitz, Shahar Goren, Gonen Golani, Yael Roichman, James B. Munro* and Raya Sorkin*,
Ebola virus (EBOV) is an enveloped virus that must fuse with the host cell membrane in order to release its genome and initiate infection. This process requires the action of the EBOV envelope glycoprotein (GP), encoded by the virus, which resides in the viral envelope and consists of a receptor binding subunit, GP1, and a membrane fusion subunit, GP2. Despite extensive research, a mechanistic understanding of the viral fusion process is incomplete. To investigate GP-membrane association, a key step in the fusion process, we used two approaches: high-throughput measurements of single-particle diffusion and single-molecule measurements with optical tweezers. Using these methods, we show that the presence of the endosomal Niemann-Pick C1 (NPC1) receptor is not required for primed GP-membrane binding. In addition, we demonstrate this binding is very strong, likely attributed to the interaction between the GP fusion loop and the membrane’s hydrophobic core. Our results also align with previously reported findings, emphasizing the significance of acidic pH in the protein–membrane interaction. Beyond Ebola virus research, our approach provides a powerful toolkit for studying other protein–membrane interactions, opening new avenues for a better understanding of protein-mediated membrane fusion events.
埃博拉病毒(EBOV)是一种包膜病毒,必须与宿主细胞膜融合才能释放其基因组并引发感染。这一过程需要病毒编码的 EBOV 包膜糖蛋白(GP)的作用,GP 位于病毒包膜中,由受体结合亚基 GP1 和膜融合亚基 GP2 组成。尽管进行了大量研究,但对病毒融合过程的机理了解仍不全面。为了研究融合过程中的关键步骤--GP-膜结合,我们采用了两种方法:高通量单粒子扩散测量法和光学镊子单分子测量法。利用这些方法,我们证明了内体 Niemann-Pick C1 (NPC1) 受体的存在并非 GP 与膜结合的必要条件。此外,我们还证明这种结合非常牢固,这可能归因于 GP 融合环和膜的疏水核心之间的相互作用。我们的结果也与之前报道的结果一致,强调了酸性 pH 在蛋白质与膜相互作用中的重要性。除埃博拉病毒研究外,我们的方法还为研究其他蛋白质与膜的相互作用提供了强大的工具包,为更好地理解蛋白质介导的膜融合事件开辟了新途径。
{"title":"Ebola Virus Glycoprotein Strongly Binds to Membranes in the Absence of Receptor Engagement","authors":"Alisa Vaknin, Alon Grossman, Natasha D. Durham, Inbal Lupovitz, Shahar Goren, Gonen Golani, Yael Roichman, James B. Munro* and Raya Sorkin*, ","doi":"10.1021/acsinfecdis.3c00622","DOIUrl":"10.1021/acsinfecdis.3c00622","url":null,"abstract":"<p >Ebola virus (EBOV) is an enveloped virus that must fuse with the host cell membrane in order to release its genome and initiate infection. This process requires the action of the EBOV envelope glycoprotein (GP), encoded by the virus, which resides in the viral envelope and consists of a receptor binding subunit, GP1, and a membrane fusion subunit, GP2. Despite extensive research, a mechanistic understanding of the viral fusion process is incomplete. To investigate GP-membrane association, a key step in the fusion process, we used two approaches: high-throughput measurements of single-particle diffusion and single-molecule measurements with optical tweezers. Using these methods, we show that the presence of the endosomal Niemann-Pick C1 (NPC1) receptor is not required for primed GP-membrane binding. In addition, we demonstrate this binding is very strong, likely attributed to the interaction between the GP fusion loop and the membrane’s hydrophobic core. Our results also align with previously reported findings, emphasizing the significance of acidic pH in the protein–membrane interaction. Beyond Ebola virus research, our approach provides a powerful toolkit for studying other protein–membrane interactions, opening new avenues for a better understanding of protein-mediated membrane fusion events.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.3c00622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841509","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}
Pub Date : 2024-04-26DOI: 10.1021/acsinfecdis.4c00173
Shu Li, Zhaopeng Wang, Shibo Song, Yuanyuan Tang, Jingjing Zhou, Xiaojing Liu, Xingjiao Zhang, Min Chang, Kairong Wang* and Yali Peng*,
Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47–57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47–57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.
{"title":"Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance","authors":"Shu Li, Zhaopeng Wang, Shibo Song, Yuanyuan Tang, Jingjing Zhou, Xiaojing Liu, Xingjiao Zhang, Min Chang, Kairong Wang* and Yali Peng*, ","doi":"10.1021/acsinfecdis.4c00173","DOIUrl":"10.1021/acsinfecdis.4c00173","url":null,"abstract":"<p >Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47–57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47–57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a <span>l</span>-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811462","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}
Pub Date : 2024-04-26DOI: 10.1021/acsinfecdis.4c00163
Sara Rossi, Valeria Tudino, Gabriele Carullo, Stefania Butini, Giuseppe Campiani* and Sandra Gemma*,
The term “zoonosis” denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low- and middle-income nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.
{"title":"Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma","authors":"Sara Rossi, Valeria Tudino, Gabriele Carullo, Stefania Butini, Giuseppe Campiani* and Sandra Gemma*, ","doi":"10.1021/acsinfecdis.4c00163","DOIUrl":"10.1021/acsinfecdis.4c00163","url":null,"abstract":"<p >The term “zoonosis” denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low- and middle-income nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811213","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}
Pub Date : 2024-04-25DOI: 10.1021/acsinfecdis.4c00091
Maëlle Duffey, Ravindra P. Jumde, Renata M.A. da Costa, Henni-Karoliina Ropponen, Benjamin Blasco and Laura J.V. Piddock*,
Efflux is a natural process found in all prokaryotic and eukaryotic cells that removes a diverse range of substrates from inside to outside. Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism utilized by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics has been considered a promising approach for antimicrobial chemotherapy over two decades, and various strategies have been employed. In this review, we provide an overview of bacterial multidrug resistance (MDR) efflux pumps, of which the resistance nodulation division (RND) efflux pumps are considered the most clinically relevant in Gram-negative bacteria, and describe over 50 efflux inhibitors that target such systems. Although numerous efflux inhibitors have been identified to date, none have progressed into clinical use because of formulation, toxicity, and pharmacokinetic issues or a narrow spectrum of inhibition. For these reasons, the development of efflux inhibitors has been considered a difficult and complex area of research, and few active preclinical studies on efflux inhibitors are in progress. However, recently developed tools, including but not limited to computational tools including molecular docking models, offer hope that further research on efflux inhibitors can be a platform for research and development of new bacterial efflux inhibitors.
{"title":"Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps","authors":"Maëlle Duffey, Ravindra P. Jumde, Renata M.A. da Costa, Henni-Karoliina Ropponen, Benjamin Blasco and Laura J.V. Piddock*, ","doi":"10.1021/acsinfecdis.4c00091","DOIUrl":"10.1021/acsinfecdis.4c00091","url":null,"abstract":"<p >Efflux is a natural process found in all prokaryotic and eukaryotic cells that removes a diverse range of substrates from inside to outside. Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism utilized by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics has been considered a promising approach for antimicrobial chemotherapy over two decades, and various strategies have been employed. In this review, we provide an overview of bacterial multidrug resistance (MDR) efflux pumps, of which the resistance nodulation division (RND) efflux pumps are considered the most clinically relevant in Gram-negative bacteria, and describe over 50 efflux inhibitors that target such systems. Although numerous efflux inhibitors have been identified to date, none have progressed into clinical use because of formulation, toxicity, and pharmacokinetic issues or a narrow spectrum of inhibition. For these reasons, the development of efflux inhibitors has been considered a difficult and complex area of research, and few active preclinical studies on efflux inhibitors are in progress. However, recently developed tools, including but not limited to computational tools including molecular docking models, offer hope that further research on efflux inhibitors can be a platform for research and development of new bacterial efflux inhibitors.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140654702","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}