878 results match your criteria Acs Infectious Diseases[Journal]


Post-translational succinylation of enoyl-CoA hydratase EchA19 slows catalytic hydration of cholesterol catabolite 3-oxo-chol-4,22-diene-24-oyl-CoA.

ACS Infect Dis 2020 Jul 10. Epub 2020 Jul 10.

Cholesterol is a major carbon source for () during infection, and cholesterol utilization plays a significant role in persistence and virulence within host macrophages. Elucidating the mechanism by which cholesterol is degraded may permit identification of new therapeutic targets. Here, we characterized EchA19 (Rv3516), an enoyl-CoA hydratase involved in cholesterol side chain catabolism. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00329DOI Listing

Electrochemical Diagnostics for Bacterial Infectious Diseases.

ACS Infect Dis 2020 Jul 11;6(7):1567-1571. Epub 2020 Jun 11.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Bacterial infections are urgent threats to human health, especially in light of rising rates of antibiotic resistance, and their ubiquity demands the development of efficient diagnostic platforms. Electrochemical biosensors for point-of-care testing are garnering interest due to their speed, sensitivity, and selectivity as well as their inexpensive, user-friendly operation. These biosensors have the potential to make significant commercial and clinical impacts. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00342DOI Listing

Call for Papers: Antiviral Therapeutics.

Authors:

ACS Infect Dis 2020 Jul 17;6(7):1527-1528. Epub 2020 Jun 17.

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http://dx.doi.org/10.1021/acsinfecdis.0c00399DOI Listing

Comprehensive Lipidomic and Metabolomic Analysis for Studying Metabolic Changes in Lung Tissue Induced by a Vaccine against Respiratory Syncytial Virus.

ACS Infect Dis 2020 Jul 6. Epub 2020 Jul 6.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in young children. Although the disease may be severe in immunocompromised, young and elderly people, there is currently no approved vaccine. We previously reported the development and immunological assessment of a novel intranasal vaccine formulation consisting of a truncated version of the RSV fusion protein (∆F) combined with a three-component adjuvant (TriAdj). Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00210DOI Listing

Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs.

ACS Infect Dis 2020 Jul 3. Epub 2020 Jul 3.

Previous efforts in our lab have led to the development of HIV-1 NNRTIs K-5a2 with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying structurally diverse motif at the right wing of the lead K-5a2 were designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (EC50 = 3. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00327DOI Listing

Structure-Interaction Relationship of Polymyxins with the Membrane of Human Kidney Proximal Tubular Cells.

ACS Infect Dis 2020 Jul 3. Epub 2020 Jul 3.

Multidrug-resistant Gram-negative bacteria are a serious global threat to human health. Polymyxins are increasingly used in patients as a last-line therapy to treat infections caused by these life-threatening 'superbugs'. Unfortunately, polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer polymyxins. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00190DOI Listing

Examining the Role of Niemann-Pick C1 Protein in the Permissiveness of Aedes Mosquitoes to Filoviruses.

ACS Infect Dis 2020 Jul 1. Epub 2020 Jul 1.

Aedes mosquitoes vector many viruses with divergent characteristics, yet the criteria needed for a virus to be vectored by an arthropod remain unknown. The intracellular cholesterol transporter protein Niemann Pick C1 (NPC1) has been identified as the necessary entry receptor for filoviruses such as Ebola and Marburg viruses. While homologs of NPC1 are observed in mosquitoes, currently no filovirus has been identified as circulating in mosquitoes. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00018DOI Listing

Evaluation of peptide-based probes towards diagnostic imaging of bacterial biofilm-associated infections.

ACS Infect Dis 2020 Jun 30. Epub 2020 Jun 30.

The clinical management of bacterial biofilm infections represents an enormous challenge in today's healthcare setting. The NIH estimates that 65% of bacterial infections are biofilm related and therapeutic outcomes are positively correlated with early intervention. Currently, there is no reliable imaging technique to detect biofilm infections and current clinical protocols for accurate and direct biofilm identification are non-existent. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00125DOI Listing

Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from .

ACS Infect Dis 2020 Jul 10. Epub 2020 Jul 10.

Department of Microbiology, Institute of Biomedical Science, University of São Paulo, Av. Prof. Lineu Prestes, 1474, São Paulo, SP 05508-000, Brazil.

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00263DOI Listing

Discovery Of Amphamide, A Drug-Candidate For The Second Generation Of Polyene Antibiotics.

ACS Infect Dis 2020 Jun 29. Epub 2020 Jun 29.

Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00068DOI Listing

Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification.

ACS Infect Dis 2020 Jun 29. Epub 2020 Jun 29.

A series of vancomycin C-terminus guanidine modifications are disclosed that improve antimicrobial activity, enhance the durability of antimicrobial action against selection or induction of resistance, and introduce a synergistic mechanism of action independent of D-Ala-D-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive, but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of D-Ala-D-Ala/D-Lac binding and display superb antimicrobial potencies (MIC 0. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00258DOI Listing

Cholesterol Constrains the Antigenic Configuration of the Membrane-Proximal Neutralizing HIV-1 Epitope.

ACS Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Biofisika Institute (CSIC, UPV/EHU), University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain.

The envelope glycoprotein (Env) enables HIV-1 cell entry through fusion of host-cell and viral membranes induced by the transmembrane subunit gp41. Antibodies targeting the C-terminal sequence of the membrane-proximal external region (C-MPER) block the fusogenic activity of gp41 and achieve neutralization of divergent HIV-1 strains and isolates. Thus, recreating the structure that generates broadly neutralizing C-MPER antibodies during infection is a major goal in HIV vaccine development. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00243DOI Listing

Progress toward the Development of Glycan-Based Vaccines against Campylobacteriosis.

ACS Infect Dis 2020 Jul 9. Epub 2020 Jul 9.

Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique (INRS), 531, boul. des Prairies, Laval, Québec H7V 1B7, Canada.

As one of the main causes of bacterial diarrhea and a major risk factor for triggering Guillain-Barré autoimmune syndrome, campylobacteriosis, that is, spp. infections, represents a major health issue worldwide. There is thus a pressing need for developing an effective and broad-coverage campylobacteriosis vaccine. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00332DOI Listing

Interaction of and Host Cells upon Infection of Bronchial Epithelium during Different Stages of Regeneration.

ACS Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, 9700 RB Groningen, The Netherlands.

The primary barrier that protects our lungs against infection by pathogens is a tightly sealed layer of epithelial cells. When the integrity of this barrier is disrupted as a consequence of chronic pulmonary diseases or viral insults, bacterial pathogens will gain access to underlying tissues. A major pathogen that can take advantage of such conditions is , thereby causing severe pneumonia. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00403DOI Listing

A Clerodane Diterpene from Resensitizes Methicillin-Resistant to β-Lactam Antibiotics.

ACS Infect Dis 2020 Jul 29;6(7):1667-1673. Epub 2020 Jun 29.

Emory University, Department of Dermatology, 615 Michael Street, Whitehead 105L, Atlanta, Georgia 30322, United States.

The rise of antibiotic resistance presents a significant healthcare challenge and precludes the use of many otherwise valuable antibiotics. One potential solution to this problem is the use of antibiotics in combination with resistance-modifying agents, compounds that act synergistically with existing antibiotics to resensitize previously resistant bacteria. In this study, 12(),16ξ-dihydroxycleroda-3,13-dien-15,16-olide, a clerodane diterpene isolated from the medicinal plant , was found to synergize with oxacillin against methicillin-resistant s. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00307DOI Listing

Structure-Activity Relationship Exploration of 3'-Deoxy-7-deazapurine Nucleoside Analogues as Anti- Agents.

ACS Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.

Human African trypanosomiasis is a neglected tropical disease caused by parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3'-deoxytubercidin (), a lead compound with activity against central-nervous-stage human African trypanosomiasis, we investigate the structure-activity relationships of the purine and ribofuranose rings. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00105DOI Listing

Characterization of a New Antienterovirus D68 Compound Purified from Avocado.

ACS Infect Dis 2020 Jul 7. Epub 2020 Jul 7.

Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, 1-2 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan.

One of the major challenges in development of antienterovirus (EV) drugs is in the safety of the drug. Here, we attempted to identify anti-EV compounds from an edible plant extract library and found potent antienterovirus D68 (EV-D68) activity in avocado (). The purified identity is determined as 2,4-(12,15)-heneicosa-12,15-diene-1,2,4-triol, named avoenin. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00404DOI Listing

Cell Surface Remodeling of under Cystic Fibrosis Airway Growth Conditions.

ACS Infect Dis 2020 Jul 2. Epub 2020 Jul 2.

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, United States.

Understanding the physiological processes underlying the ability of to become a chronic pathogen of the cystic fibrosis (CF) lung is important to the development of prophylactic and therapeutic strategies to better control and treat pulmonary infections caused by these bacteria. Gene expression profiling of a diversity of complex isolates points to amino acids being significant sources of carbon and energy for in both CF sputum and synthetic CF medium and to the bacterium undergoing an important metabolic reprogramming in order to adapt to this particular nutritional environment. Cell envelope analyses conducted on the same representative isolates further revealed unexpected structural alterations in major cell surface glycolipids known as the glycopeptidolipids (GPLs). Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00214DOI Listing

Gallium(III)-Salophen as a Dual Inhibitor of Heme Sensing and Iron Acquisition.

ACS Infect Dis 2020 Jul 6. Epub 2020 Jul 6.

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States.

is an opportunistic bacterium that causes life-threatening infections in immunocompromised patients. In infection, it uses heme as a primary iron source and senses the availability of exogenous heme through the heme assimilation system (Has), an extra cytoplasmic function σ-factor system. A secreted hemophore HasAp scavenges heme and, upon interaction with the outer-membrane receptor HasR, activates a signaling cascade, which in turn creates a positive feedback loop critical for sensing and adaptation within the host. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00138DOI Listing

Photodynamic Inactivation of ESKAPE Group Bacterial Pathogens in Planktonic and Biofilm Cultures Using Metallated Porphyrin-Doped Conjugated Polymer Nanoparticles.

ACS Infect Dis 2020 Jun 30. Epub 2020 Jun 30.

Instituto de Investigaciones en Tecnologı́as Energéticas y Materiales Avanzados (IITEMA), Universidad Nacional de Rı́o Cuarto, Consejo Nacional de Investigaciones Cientı́ficas y Tecnológicas (CONICET), Rı́o Cuarto, Córdoba X5804BYA, Argentina.

Photodynamic inactivation (PDI) protocols using photoactive metallated porphyrin-doped conjugated polymer nanoparticles (CPNs) and blue light were developed to eliminate multidrug-resistant pathogens. CPNs-PDI protocols using varying particle concentrations and irradiation doses were tested against nine pathogenic bacterial strains including antibiotic-resistant bacteria of the ESKAPE (, , , , , and ) pathogens group. The bactericidal effect was achieved in methicillin-resistant () strains using low light doses (9. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00268DOI Listing

Achieving Regulatory Alignment for Anti-Infective Clinical Trials.

ACS Infect Dis 2020 Jun;6(6):1308-1310

Office of International Programs, Pharmaceuticals and Medical Devices Agency, Tokyo 100-0013, Japan.

The growing concern of antimicrobial resistance coupled with the dearth of new antibacterial agents in development is a major public health threat. Multiple stakeholder efforts are underway to address the various challenges facing this field; while some progress has been made, antibacterial drug development continues to be a challenging area. The economic issues encountered in this space are probably today the most cogent; however, there are many other aspects that continue to pose challenges to enterprises engaging in this area, from the difficulties in discovering and advancing new classes of products to scientific issues with clinical trial design and feasibility in conducting these trials. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00270DOI Listing

Fostering Antibiotic Development through Impact Funding.

Authors:
Aleks Engel

ACS Infect Dis 2020 Jun;6(6):1311-1312

REPAIR Impact Fund, Novo Holdings, Hellerup, Denmark 2900.

New antibiotics are critical to staying ahead of antimicrobial resistance, yet the return on investment in anti-infective development is a serious obstacle to commercial research. The REPAIR Impact Fund is designed to foster continued innovation until structural changes in the market provide sufficient incentives for investment. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00069DOI Listing

Personal View of the Antibiotic Value Proposition.

Authors:
David M Shlaes

ACS Infect Dis 2020 Jun;6(6):1315-1316

Stonington, Connecticut 06378, United States.

In this brief viewpoint, I present four examples from my life in the practice of medicine and infectious diseases that illustrate both the miracle of antibiotics and the despair when they fail. There is the patient with pneumococcal pneumonia that was rapidly cured but also a disastrous outbreak of highly resistant infection in a ward of severely burned patients where antibiotic treatment was ultimately futile. I note the utility of a new antibiotic in treating otherwise highly resistant infections. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00060DOI Listing

How to Stimulate and Facilitate Early Stage Antibiotic Discovery.

ACS Infect Dis 2020 Jun;6(6):1302-1304

Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072 Australia.

The discovery of novel antibiotics is essential to combat the rise of antimicrobial resistance. While a number of initiatives are focused on advancing promising leads into the clinic, there is a dearth of effort at stimulating the early stage discovery. We present one pathway that has successfully demonstrated an ability to revitalize fundamental research and reengage researchers. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00163DOI Listing

On the Road to Discovering Urgently Needed Antibiotics: So Close Yet So Far Away.

ACS Infect Dis 2020 Jun;6(6):1292-1294

The Pew Charitable Trusts, 901 E. Street N.W., Washington, D.C. 20004, United States.

The Pew Charitable Trusts' 2016 publication "A Scientific Roadmap for Antibiotic Discovery" provided a consensus approach to accelerating the discovery of novel antibiotics targeting Gram-negative pathogens. Since then, encouraging initiatives have launched to catalyze antibiotics discovery, particularly by improving knowledge sharing and making discovery efforts more efficient and effective. However, because the global pipeline remains insufficient to address current and future unmet needs, existing initiatives are not enough. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00100DOI Listing

A View from the Wellcome Trust Drug-Resistant Infections Priority Programme: Creating a Sustainable Research and Development Ecosystem to Meet the Global Need for Antibiotics.

ACS Infect Dis 2020 Jun;6(6):1305-1307

Drug-Resistant Infections Priority Programme, Wellcome Trust, London NW1 2BE, U.K.

Antibiotics have been a key component of modern medicine for decades. A critical question is why not enough antibacterials are being developed to tackle the growing challenge of drug-resistant infections. While current innovation in the early preclinical pipeline is encouraging, the journey for any new antibiotic is burdened with multiple challenges across its early and late development path. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00094DOI Listing

Antibacterial Drugs: The Last Frontier.

Authors:
David M Shlaes

ACS Infect Dis 2020 Jun;6(6):1313-1314

Stonington, Connecticut 06378, United States.

Our pipeline of antibacterial drugs is woefully lacking in our most high priority areas of medical need. In the absence of a reasonable return on their investment in antibacterial drugs, large companies have, for the most part, abandoned the area. Private investment in the research and development of these agents is plummeting, and public support, while important, cannot entirely replace this loss. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00057DOI Listing

NIAID's Comprehensive Support Mechanisms for Antibiotic Development.

ACS Infect Dis 2020 Jun;6(6):1299-1301

Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, 5601 Fishers Lane, Bethesda, Maryland 20892, United States.

The National Institute of Allergy and Infectious Diseases (NIAID) recognizes the continuing threat of antimicrobial resistance and the need to develop new therapeutics and strategies to combat multidrug resistant organisms. NIAID leverages multiple mechanisms to help support antibiotic developers struggling in the "valley of death" of preclinical antibiotic development. The Division of Microbiology and Infectious Diseases' (DMID) preclinical services are a comprehensive set of services to facilitate efforts to develop vaccines, diagnostics, and therapeutics for a broad array of bacterial, viral, fungal, and parasitic pathogens. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00099DOI Listing

and Characterization of the Anti-Zika Virus Activity of ProTides of 2'-C-β-Methylguanosine.

ACS Infect Dis 2020 Jul 19;6(7):1650-1658. Epub 2020 Jun 19.

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.

The ProTide approach has emerged as a powerful tool to improve the intracellular delivery of nucleotide analogs with antiviral and anticancer activity. Here, we characterized the anti-ZIKV (ZIKV, Zika virus) activity of two ProTides of 2'-C-β-methylguanosine. ProTide is a 2'-C-β-methylguanosine tryptamine phosphoramidate monoester, and ProTide is a 2-(methylthio)-ethyl-2'-C-β-methylguanosine tryptamine phosphoramidate diester. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00091DOI Listing

Antibacterial Anacardic Acid Derivatives.

ACS Infect Dis 2020 Jul 28;6(7):1674-1685. Epub 2020 Jun 28.

Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germany.

We report on the antibacterial activity of five phenolic lipids derived from anacardic acid characterized by increasing alkyl chain lengths with 6, 8, 10, 12, or 14 carbon atoms. The compounds were profiled for their physicochemical properties, transport across epithelial monolayers, cytotoxicity, and antibacterial activity as compared to common antibiotics. No cytotoxicity was reported in cell lines of fibroblast, hepatic, colorectal, or renal origin. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00378DOI Listing

Biofilm Eradication via Nitric Oxide-Releasing Cyclodextrins.

ACS Infect Dis 2020 Jul 23;6(7):1940-1950. Epub 2020 Jun 23.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

is the main contributor to the morbidity and mortality of cystic fibrosis (CF) patients. Chronic respiratory infections are rarely eradicated due to protection from CF mucus and the biofilm matrix. The composition of the biofilm matrix determines its viscoelastic properties and affects antibiotic efficacy. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00246DOI Listing

1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of β-Lactamase Inhibitors against Cephalosporinase.

ACS Infect Dis 2020 Jul 24;6(7):1965-1975. Epub 2020 Jun 24.

Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy.

Boronic acid transition state inhibitors (BATSIs) are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific BATSIs bearing an amide side chain mimicking the β-lactam's amide side chain are an established and recognized synthetic strategy. Herein, we describe a new class of BATSIs where the amide group is replaced by a bioisostere triazole; these compounds were designed as molecular probes. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00254DOI Listing

HSF1 Activation Can Restrict HIV Replication.

ACS Infect Dis 2020 Jul 10;6(7):1659-1666. Epub 2020 Jun 10.

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1 transcription factor activity from cytotoxic proteostasis stress and thereby better elucidate the proposed role(s) of HSF1 in the HIV-1 lifecycle. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00166DOI Listing

Peptide Methionine Sulfoxide Reductase from Is Required for Protection against HOCl and Affects the Host Response to Infection.

ACS Infect Dis 2020 Jul 22;6(7):1928-1939. Epub 2020 Jun 22.

Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia.

Peptide methionine sulfoxide reductases (Msrs) are enzymes that repair ROS-damage to sulfur-containing amino acids such as methionine, ensuring functional integrity of cellular proteins. Here we have shown that unlike the majority of pro- and eukaryotic Msrs, the peptide methionine sulfoxide reductase (MsrAB) from the human pathobiont (Hi) is required for the repair of hypochlorite damage to cell envelope proteins, but more importantly, we were able to demonstrate that MsrAB plays a role in modulating the host immune response to Hi infection. Loss of MsrAB resulted in >1000-fold increase in sensitivity of Hi to HOCl-mediated killing, and also reduced biofilm formation and in-biofilm survival. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00242DOI Listing

Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen .

ACS Infect Dis 2020 Jul 24;6(7):1976-1997. Epub 2020 Jun 24.

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.

Tilimycin is an enterotoxin produced by the opportunistic pathogen that causes antibiotic-associated hemorrhagic colitis (AAHC). This pyrrolobenzodiazepine (PBD) natural product is synthesized by a bimodular nonribosomal peptide synthetase (NRPS) pathway composed of three proteins: NpsA, ThdA, and NpsB. We describe the functional and structural characterization of the fully reconstituted NRPS system and report the steady-state kinetic analysis of all natural substrates and cofactors as well as the structural characterization of both NpsA and ThdA. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354218PMC

Current Perspective of Antiviral Strategies against COVID-19.

ACS Infect Dis 2020 Jul 16;6(7):1624-1634. Epub 2020 Jun 16.

NUSMed Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.

COVID-19 was declared a pandemic by the World Health Organization on March 11, 2020. This novel coronavirus disease, caused by the SARS-CoV-2 virus, has resulted in severe and unprecedented social and economic disruptions globally. Since the discovery of COVID-19 in December 2019, numerous antivirals have been tested for efficacy against SARS-CoV-2 and also clinically to treat this disease. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299369PMC

Conserved Conformational Changes in the Regulation of MazEF-mt1.

ACS Infect Dis 2020 Jul 16;6(7):1783-1795. Epub 2020 Jun 16.

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China.

Toxin-antitoxin (TA) systems, which regulate many important cellular processes, are abundantly present in prokaryotic organisms. MazEF is a common type of TA system implicated in the formation of "persisters cells" of the pathogen , which contains 10 such systems. However, the exact function and inhibition mode of each MazF protein are not quite understood. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00048DOI Listing

COVID-19 and Other Pandemics: How Might They Be Prevented?

ACS Infect Dis 2020 Jul 1;6(7):1563-1566. Epub 2020 Jun 1.

Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.

Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and now Coronavirus Disease 2019 (COVID-19) have arisen, and given the current absence of highly effective approved vaccines or drugs, brute-force approaches involving physical barriers are being used to counter virus spread. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269098PMC

Synthesis, Structure-Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity.

ACS Infect Dis 2020 Jul 15;6(7):1951-1964. Epub 2020 Jun 15.

Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.

Phenotypic whole-cell screening against () in glycerol-alanine-salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone which was optimized for solubility by replacing the sulfone moiety with a sulfoxide . The synthesis and structure-activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound displayed favorable properties and was therefore selected for pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone . Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00252DOI Listing

Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients.

Authors:
Alexey Polonikov

ACS Infect Dis 2020 Jul 28;6(7):1558-1562. Epub 2020 May 28.

Department of Biology, Medical Genetics and Ecology and Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russian Federation.

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077PMC

Investigations into the Antibacterial Mechanism of Action of Viridicatumtoxins.

ACS Infect Dis 2020 Jul 4;6(7):1759-1769. Epub 2020 Jun 4.

Department of Microbiology and Immunology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.

Viridicatumtoxins are a rare class of tetracycline-like antibiotics that strongly inhibit drug-resistant Gram-positive bacteria. Although reported to exhibit inhibition activity to undecaprenyl pyrophosphate synthase (UPPS), an essential enzyme in bacterial cell wall synthesis, the biological targets and mechanism of action of viridicatumtoxins, especially the drug-target interactions, remain largely unknown. In this study, the structure of UPPS (UPPS) was first determined, uncovering that UPPS can form not only a typical functional dimer but also an unexpected atypical dimer. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00031DOI Listing

Small Molecule Sensors Targeting the Bacterial Cell Wall.

ACS Infect Dis 2020 Jul 9;6(7):1587-1598. Epub 2020 Jun 9.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, United States.

This review highlights recent efforts to detect bacteria using engineered small molecules that are processed and incorporated similarly to their natural counterparts. There are both scientific and clinical justifications for these endeavors. The use of detectable, cell-wall targeted chemical probes has elucidated microbial behavior, with several fluorescent labeling methods in widespread laboratory use. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00515DOI Listing

Small Molecule Inhibitors Targeting the Interaction of Ricin Toxin A Subunit with Ribosomes.

ACS Infect Dis 2020 Jul 8;6(7):1894-1905. Epub 2020 Jun 8.

Department of Plant Biology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, New Jersey 08901, United States.

Ricin toxin A subunit (RTA) removes an adenine from the universally conserved sarcin/ricin loop (SRL) on eukaryotic ribosomes, thereby inhibiting protein synthesis. No high affinity and selective small molecule therapeutic antidotes have been reported against ricin toxicity. RTA binds to the ribosomal P stalk to access the SRL. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00127DOI Listing

Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease.

ACS Infect Dis 2020 Jun 4. Epub 2020 Jun 4.

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, is a novel human betacoronavirus that is rapidly spreading worldwide. The outbreak currently includes over 3.7 million cases and 260,000 fatalities. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274171PMC

Effective Strategy Targeting Polymyxin-Resistant Gram-Negative Pathogens: Polymyxin B in Combination with the Selective Serotonin Reuptake Inhibitor Sertraline.

ACS Infect Dis 2020 Jun 25;6(6):1436-1450. Epub 2020 May 25.

Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.

This study aimed to investigate synergistic antibacterial activity of polymyxin B in combination with the selective serotonin reuptake inhibitor, sertraline, against the Gram-negative pathogens , , and . The combination of polymyxin B and sertraline showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. The potential antimicrobial mode of action of the combination was investigated against FADDI-PA024 using untargeted metabolomics alongside scanning and transmission electron microscopy (EM). Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00108DOI Listing

Nerve Growth Factor Confers Neuroprotection against Colistin-Induced Peripheral Neurotoxicity.

ACS Infect Dis 2020 Jun 21;6(6):1451-1459. Epub 2020 May 21.

College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.

Neurotoxicity is an unwanted side effect for patients when receiving parenteral colistin therapy. The development of effective neuroprotective agents that can be coadministered during colistin therapy remains a priority area in antimicrobial chemotherapy. The present study aimed to investigate the protective effect of nerve growth factor (NGF) against colistin-induced peripheral neurotoxicity using a murine model. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00107DOI Listing

IL-1β Enhances the Antiviral Effect of IFN-α on HCV Replication by Negatively Modulating ERK2 Activation.

ACS Infect Dis 2020 Jul 1;6(7):1708-1718. Epub 2020 Jun 1.

CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.

Chronic hepatitis C infection is a leading cause of liver cirrhosis, which is linked to chronic hepatic inflammation. While there are multiple studies detailing the proinflammatory role of interleukin-1β (IL-1β) in HCV-induced inflammasome signaling, the antiviral capacity of this cytokine has not been adequately investigated in the context of HCV infection or other members of Flaviridae. Our data indicated that IL-1β alone does not inhibit HCV replication, yet when in combination with IFN-α, it can boost the anti-HCV activity of IFN-α, which is mediated by augmented STAT1 tyrosine 701 phosphorylation. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00506DOI Listing

Potency Increase of Spiroketal Analogs of Membrane Inserting Indolyl Mannich Base Antimycobacterials Is Due to Acquisition of MmpL3 Inhibition.

ACS Infect Dis 2020 Jul 29;6(7):1882-1893. Epub 2020 May 29.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545 Singapore.

Chemistry campaigns identified amphiphilic indolyl Mannich bases as novel membrane-permeabilizing antimycobacterials. Spiroketal analogs of this series showed increased potency, and the lead compound displayed efficacy in a mouse model of tuberculosis. Yet the mechanism by which the spiroketal moiety accomplished the potency "jump" remained unknown. Read More

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http://dx.doi.org/10.1021/acsinfecdis.0c00121DOI Listing