559 results match your criteria Acs Infectious Diseases[Journal]


Multimodal tracking of (controlled) Staphylococcus aureus infections in mice.

ACS Infect Dis 2019 Apr 24. Epub 2019 Apr 24.

There is a need to develop diagnostic and analytical tools that allow non-invasive monitoring of bacterial growth/dissemination in vivo. For such cell-tracking studies to hold translational value to controlled human infections, in which volunteers are experimentally colonized, they should not require genetic modification and allow tracking over a number of replication cycles. To gauge if an antimicrobial peptide tracer 99mTc-UBI29-41-Cy5, which contains both a fluorescent and radioactive moiety, could be used for such in vivo bacterial tracking, we performed longitudinal imaging of a thigh muscle infection with 99mTc-UBI29-41-Cy5 labelled Staphylococcus aureus. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00015DOI Listing

A short cationic peptide derived from Archaea with dual antibacterial properties and anti-infective potential.

ACS Infect Dis 2019 Apr 24. Epub 2019 Apr 24.

Bacterial biofilms and associated infections represent one of the biggest challenges in the clinic and as an alternative to counter bacterial infections the antimicrobial peptides have attracted great attention in the last decade. Here, ten short cationic antimicrobial peptides were generated through sliding-window based on the 18-amino acid residues peptide, derived from a Pyrobaculum aerophilum ribosomal protein. PaDBS1R6F10 exhibited anti-infective potential as it decreased the bacterial burden in murine Pseudomonas aeruginosa cutaneous infections by more than 1000-fold. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00073DOI Listing

Small-molecule inhibitors of Haemophilus influenzae IgA1 protease.

ACS Infect Dis 2019 Apr 24. Epub 2019 Apr 24.

Newly identified, non-typable H. influenza strains represent a serious threat to global health. Due to the increasing prevalence of antibiotic resistance, virulence factors have emerged as potential therapeutic targets that would be less likely to promote resistance. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00004DOI Listing

Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis.

ACS Infect Dis 2019 Apr 24. Epub 2019 Apr 24.

This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 4. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00325DOI Listing

The Mce3R stress-resistance pathway is vulnerable to small molecule targeting that improves tuberculosis drug activities.

ACS Infect Dis 2019 Apr 23. Epub 2019 Apr 23.

One-third of the world's population carries Mycobacterium tuberculosis (Mtb), the infectious agent that causes tuberculosis (TB), and every 17 seconds someone dies of TB. After infection, Mtb can live dormant for decades in a granuloma structure arising from the host immune response; and cholesterol is important for this persistence of Mtb. Current treatments require long-duration drug regimens with many associated toxicities, which are compounded by the high doses required. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00099DOI Listing

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine Reductase 1 Inhibitors.

ACS Infect Dis 2019 Apr 23. Epub 2019 Apr 23.

Cycloguanil is a known dihydrofolate reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was develop, resulting in 1 and 2a having IC50 of 692 and 186 nM, respectively, towards TbPTR1. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00358DOI Listing

Antibacterial Activity and Mode of Action of a Sulfonamide-Based Class of Oxaborole Leucyl-tRNA Synthetase Inhibitors.

ACS Infect Dis 2019 Apr 22. Epub 2019 Apr 22.

Benzoxaboroles are a class of boron-containing compounds with a broad range of biological activities. A subset of benzoxaboroles have antimicrobial activity due primarily to their ability to inhibit leucyl-tRNA synthetase (LeuRS) via the oxaborole tRNA trapping mechanism, which involves formation of a stable tRNALeu-benzoxaborole adduct in which the boron atom interacts with the 2- and 3-oxygen atoms of the 3-terminal tRNA adenosine. We sought to identify other antibacterial targets for this promising class of compounds by means of mode of action studies, and we selected a nitrophenyl sulfonamide-based oxaborole (PT638) as a probe molecule because it had potent antibacterial activity (MIC of 0. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00071DOI Listing

Small Molecule Potentiation of Gram-positive Selective Antibiotics Against Acinetobacter baumannii.

ACS Infect Dis 2019 Apr 19. Epub 2019 Apr 19.

In 2016, the World Health Organization deemed antibiotic resistance one of the biggest threats to global health, food security, and development. The need for new methods to combat infections caused by antibiotic resistant pathogens will require a variety of approaches to identifying effective new therapeutic strategies. One approach is the identification of small molecule adjuvants that potentiate the activity of antibiotics of demonstrated utility, whose efficacy is abated by resistance, both acquired and intrinsic. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00067
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http://dx.doi.org/10.1021/acsinfecdis.9b00067DOI Listing
April 2019
1 Read

Hijacking the Bacterial Circuitry of Biofilm Processes via Chemical "Hot-Wiring": An Under-explored Avenue for Therapeutic Development.

ACS Infect Dis 2019 Apr 19. Epub 2019 Apr 19.

Department of Chemistry , Emory University , 1515 Dickey Drive , Atlanta , Georgia 30322 , United States.

Biofilm-associated infections are linked to chronic and recurring illnesses. These infections are often not susceptible to current antibiotic treatments because of the protective exocellular matrix and subpopulations of dormant or "persister" cells. Targeting bacterial circuitry involved in biofilm formation, including two-component systems, quorum sensing, polysaccharide structural integrity, and cyclic nucleotide signaling pathways, has the potential to expand the existing arsenal of therapeutics, thus catalyzing a second golden age of antibiotic development. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00104DOI Listing

High-resolution structure of ClpC1-rufomycin and ligand binding studies provide a framework to design and optimize anti-TB leads.

ACS Infect Dis 2019 Apr 16. Epub 2019 Apr 16.

Addressing the urgent need to develop novel drugs against drug-resistant Mycobacterium tuberculosis (M. tb) strains, ecumicin (ECU) and rufomycin I (RUFI) are being explored as promising new leads targeting cellular proteostasis via the caseinolytic protein ClpC1. Details of the binding topology and chemical mode of (inter-)action of these cyclopeptides help drive further development of novel potency-optimized entities as tuberculosis drugs. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00276DOI Listing

Dissecting the Components of Sindbis Virus from Arthropod and Vertebrate Hosts: Implications for Infectivity Differences.

ACS Infect Dis 2019 Apr 15. Epub 2019 Apr 15.

Department of Chemistry , Indiana University , 800 East Kirkwood Avenue , Bloomington , Indiana 47405 , United States.

Sindbis virus (SINV) is an enveloped, single-stranded RNA virus, which is transmitted via mosquitos to a wide range of vertebrate hosts. SINV produced by vertebrate, baby hamster kidney (BHK) cells is more than an order of magnitude less infectious than SINV produced from mosquito (C6/36) cells. The cause of this difference is poorly understood. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00356
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http://dx.doi.org/10.1021/acsinfecdis.8b00356DOI Listing
April 2019
2 Reads

Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase.

ACS Infect Dis 2019 Apr 23. Epub 2019 Apr 23.

Instituto de Química Médica (IQM-CSIC) , Madrid E-28006 , Spain.

Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an α-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase ( Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here, we describe our first steps toward the design of nonpeptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00355
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http://dx.doi.org/10.1021/acsinfecdis.8b00355DOI Listing
April 2019
1 Read

Label-Free Proteomic Analysis Reveals Parasite-Specific Protein Alterations in Macrophages Following Leishmania amazonensis, Leishmania major, or Leishmania infantum Infection.

ACS Infect Dis 2019 Apr 23. Epub 2019 Apr 23.

Department of Chemical Physiology , The Scripps Research Institute , 10550 North Torrey Pines Road, SR302 , La Jolla , California 92037 , United States.

Leishmania is an obligate intracellular parasite known to modulate the host cell to survive and proliferate. However, the complexity of host-parasite interactions remains unclear. Also, the outcome of the disease has been recognized to be species-specific and dependent on the host's immune responses. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00338DOI Listing

N-Methylation of Amino Acids in Gelatinase Biosynthesis-Activating Pheromone Identifies Key Site for Stability Enhancement with Retention of the Enterococcus faecalis fsr Quorum Sensing Circuit Response.

ACS Infect Dis 2019 Apr 19. Epub 2019 Apr 19.

Department of Chemistry , University of Nevada, Reno , 1664 N. Virginia Street , Reno , Nevada 89557 , United States.

The growing prevalence of multiantibiotic-resistant bacteria necessitates looking at potential alternative approaches for attenuating infections by bacteria while reducing the rate of antibiotic resistance development. Enterococcus faecalis is responsible for a large percentage of clinical enterococci infections, and its pathogenicity has been demonstrated to be influenced by quorum sensing (QS). In this study, we report the systematic study of the relationship between backbone hydrogens and the ability to activate the FsrC receptor. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00097
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http://dx.doi.org/10.1021/acsinfecdis.9b00097DOI Listing
April 2019
2 Reads

Signed, Sealed, Delivered: Conjugate and Prodrug Strategies as Targeted Delivery Vectors for Antibiotics.

ACS Infect Dis 2019 Apr 10. Epub 2019 Apr 10.

Department of Chemistry , Emory University , 1515 Dickey Drive , Atlanta , Georgia 30322 , United States.

Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00019DOI Listing
April 2019
1 Read

Detecting Vertical Zika Transmission: Emerging Diagnostic Approaches for an Emerged Flavivirus.

ACS Infect Dis 2019 Apr 17. Epub 2019 Apr 17.

Department of Medicine, Division of Infectious Diseases , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.

Zika virus (Zika) was recently responsible for a massive epidemic that spread throughout Latin America and beyond. Though Zika is typically asymptomatic or self-limiting, the sheer numbers of Zika infections led to the identification of unexpected phenotypes including sexual transmission, Guillain-Barré syndrome, and teratogenicity. Thousands of infants in South, Central, and North America have now been born with microcephaly or one of a number of fetal anomalies constituting the congenital Zika syndrome (CZS). Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00003
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http://dx.doi.org/10.1021/acsinfecdis.9b00003DOI Listing
April 2019
8 Reads

Active-Site Druggability of Carbapenemases and Broad-Spectrum Inhibitor Discovery.

ACS Infect Dis 2019 Apr 15. Epub 2019 Apr 15.

Department of Molecular Medicine , University of South Florida College of Medicine , 12901 Bruce B. Downs Blvd, MDC 3522 , Tampa , Florida 33612 , United States.

Serine and metallo-carbapenemases are a serious health concern due to their capability to hydrolyze nearly all β-lactam antibiotics. However, the molecular basis for their unique broad-spectrum substrate profile is poorly understood, particularly for serine carbapenemases, such as KPC-2. Using substrates and newly identified small molecules, we compared the ligand binding properties of KPC-2 with the noncarbapenemase CTX-M-14, both of which are Class A β-lactamases with highly similar active sites. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00052DOI Listing
April 2019
2 Reads

Synergy between Synthetic Antimicrobial Polymer and Antibiotics: A Promising Platform To Combat Multidrug-Resistant Bacteria.

ACS Infect Dis 2019 Apr 11. Epub 2019 Apr 11.

Centre for Advanced Macromolecular Design (CAMD) and Australian Centre for NanoMedicine (ACN), School of Chemical Engineering , University of New South Wales-Sydney , Building E8, Gate 2, High Street , Kensington, Sydney , New South Wales 2052 , Australia.

The failure of many antibiotics in the treatment of chronic infections caused by multidrug-resistant (MDR) bacteria necessitates the development of effective strategies to combat this global healthcare issue. Here, we report an antimicrobial platform based on the synergistic action between commercially available antibiotics and a potent synthetic antimicrobial polymer that consists of three key functionalities: low-fouling oligoethylene glycol, hydrophobic ethylhexyl, and cationic primary amine groups. Checkerboard assays with Pseudomonas aeruginosa ( P. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00049DOI Listing
April 2019
2 Reads

Synthesis and Evaluation of QS-7-Based Vaccine Adjuvants.

ACS Infect Dis 2019 Mar 28. Epub 2019 Mar 28.

We have designed and synthesized two analogs (5 and 6) of QS-7, a natural saponin compound isolated from Quillaja saponaria (QS) Molina tree bark. The only structural difference between compound 5 and 6 is that 5 is acetylated at the 3- and 4-O positions of the quillaic acid C28 fucosyl unit while 6 is not. However, the two analogs show significantly different immunostimulant profiles. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00039
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http://dx.doi.org/10.1021/acsinfecdis.9b00039DOI Listing
March 2019
1 Read

Poliovirus Evolution toward Independence from the Phosphatidylinositol-4 Kinase III β/Oxysterol-Binding Protein Family I Pathway.

ACS Infect Dis 2019 Apr 5. Epub 2019 Apr 5.

Université Côte d'Azur, CNRS , Institut de Pharmacologie Moléculaire et Cellulaire , 660 route des lucioles , Valbonne 06560 , France.

Phosphatidylinositol-4 kinase III β (PI4KB) and oxysterol-binding protein (OSBP) family I provide a conserved host pathway required for enterovirus replication. Here, we analyze the role and essentiality of this pathway in enterovirus replication. Phosphatidylinositol 4-phosphate (PI4P) production and cholesterol accumulation in the replication organelle (RO) are severely suppressed in cells infected with a poliovirus (PV) mutant isolated from a PI4KB-knockout cell line (RD[Δ PI4KB]). Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00038DOI Listing
April 2019
5 Reads

Nitrooxidoreductase Rv2466c-Dependent Fluorescent Probe for Mycobacterium tuberculosis Diagnosis and Drug Susceptibility Testing.

ACS Infect Dis 2019 Apr 10. Epub 2019 Apr 10.

School of Pharmaceutical Sciences , Tsinghua University , Haidian District, Beijing 100084 , P. R. China.

Firstly, this study demonstrated that natural product-inspired coumarin-based nitrofuranyl calanolides (NFCs) can form the Rv2466c-mycothiol (MSH)-NFC (RvMN) ternary complex via NFC binding to W21, N51, and Y61 of Rv2466c and be specifically reduced by Rv2466c, which is accompanied by the generation of a high level of fluorescence. Additionally, the results unveiled that the acetylated cysteine-glucosamine (AcCys-GlcN) motif of MSH is sufficient to interact with Rv2466c and adopt the active conformation that is essential for fully reducing NFCs. Further clinical translational investigation in this Article indicated that the novel fluorescent NFC probe can serve as a much needed high-throughput and low-cost detection method for detection of living Mycobacterium tuberculosis ( Mtb) and can precisely determine MIC values for a full range of available drugs. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00006
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http://dx.doi.org/10.1021/acsinfecdis.9b00006DOI Listing
April 2019
7 Reads

LRRK2 in Infection: Friend or Foe?

ACS Infect Dis 2019 Apr 5. Epub 2019 Apr 5.

Host-Pathogen Interactions in Tuberculosis Laboratory , The Francis Crick Institute , 1 Midland Road , London NW1 1AT , United Kingdom.

In the field of Parkinson's disease (PD) research, leucine-rich repeat kinase 2 (LRRK2) remains one of the most enigmatic kinases. LRRK2 pathogenic mutations result in increased kinase activity, making LRRK2 an attractive therapeutic target for PD. For over 10 years, the identification of a bona fide substrate and a physiological function for LRRK2 has been elusive, and only recently, Rab GTPases were identified as substrates for LRRK2 kinase activity. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00051DOI Listing

Interaction of a Model Peptide on Gram Negative and Gram Positive Bacterial Sliding Clamps.

ACS Infect Dis 2019 Apr 5. Epub 2019 Apr 5.

Université de Strasbourg , CNRS, Architecture et Réactivité de l'ARN, UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS , 15 rue René Descartes , F-67000 Strasbourg , France.

Bacterial sliding clamps control the access of DNA polymerases to the replication fork and are appealing targets for antibacterial drug development. It is therefore essential to decipher the polymerase-clamp binding mode across various bacterial species. Here, two residues of the E. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.9b00089
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http://dx.doi.org/10.1021/acsinfecdis.9b00089DOI Listing
April 2019
3 Reads

Modifications on C6 and C7 Positions of 3-Phenylquinolone Efflux Pump Inhibitors Led to Potent and Safe Antimycobacterial Treatment Adjuvants.

ACS Infect Dis 2019 Apr 4. Epub 2019 Apr 4.

Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy.

Nontuberculous mycobacteria (NTM) are ubiquitous microbes belonging to the Mycobacterium genus. Among all NTM pathogens, M. avium is one of the most frequent agents causing pulmonary disease, especially in immunocompromised individuals and cystic fibrosis patients. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00041DOI Listing
April 2019
1 Read

Toward Curative Immunomodulation Strategies for Chronic Hepatitis B Virus Infection.

ACS Infect Dis 2019 Apr 3. Epub 2019 Apr 3.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital , Southern Medical University , No. 1838, North Guangzhou Avenue , Guangzhou , Guangdong 510515 , China.

Chronic hepatitis B virus (HBV) infection remains a major cause of morbidity and mortality worldwide. HBV surface antigen loss is considered a functional cure and is an ideal goal for antiviral therapy. However, current treatment regimens, including nucleos(t)ide analogues or interferons monotherapy and combination therapy, rarely achieve this goal in chronic hepatitis B patients. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00297
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http://dx.doi.org/10.1021/acsinfecdis.8b00297DOI Listing
April 2019
3 Reads

Treatment of Chronic Hepatitis B Virus Infection Using Small Molecule Modulators of Nucleocapsid Assembly: Recent Advances and Perspectives.

ACS Infect Dis 2019 Mar 29. Epub 2019 Mar 29.

Institute of Virology , University Hospital Essen, University Duisburg Essen , Hufelandstrasse 55 , Essen 45122 , Germany.

On the basis of the recent advance of basic research on molecular biology of hepatitis B virus (HBV) infection, novel antiviral drugs targeting various steps of the HBV life cycle have been developed in recent years. HBV nucleocapsid assembly is now recognized as a hot target for anti-HBV drug development. Structural and functional analysis of HBV nucleocapsid allowed rational design and improvement of small molecules with the ability to interact with the components of HBV nucleocapsid and modulate the viral nucleocapsid assembly process. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00337DOI Listing
March 2019
1 Read

Direct Inhibition of MmpL3 by Novel Antitubercular Compounds.

ACS Infect Dis 2019 Mar 28. Epub 2019 Mar 28.

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

MmpL3, an essential transporter involved in the export of mycolic acids, is the proposed target of a number of antimycobacterial inhibitors under development. Whether MmpL3 serves as the direct target of these compounds, however, has been called into question after the discovery that some of them dissipated the proton motive force from which MmpL transporters derive their energy. Using a combination of in vitro and whole-cell-based approaches, we here provide evidence that five structurally distinct MmpL3 inhibitor series, three of which impact proton motive force in Mycobacterium tuberculosis, directly interact with MmpL3. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00048DOI Listing
March 2019
1 Read

Development of Radioiodinated Benzofuran Derivatives for in Vivo Imaging of Prion Deposits in the Brain.

ACS Infect Dis 2019 Mar 27. Epub 2019 Mar 27.

Department of Hygienic Chemistry, Graduate School of Biomedical Sciences , Nagasaki University , 1-14 Bunkyo-machi , Nagasaki 852-8521 , Japan.

Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrP) in the brain tissue. Here, we report the development of I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrP deposits. We synthesized and radioiodinated several 5-IBF and 6-IBF derivatives. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00184DOI Listing
March 2019
5 Reads

Structural Insight into the Mechanism of Staphylococcus aureus Stp1 Phosphatase.

ACS Infect Dis 2019 Mar 25. Epub 2019 Mar 25.

State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , P. R. China.

Staphylococcus aureus Stp1, which belongs to the bacterial metal-dependent protein phosphatase (PPM) family, is a promising candidate for antivirulence targeting. How Stp1 recognizes the phosphorylated peptide remains unclear, however. In order to investigate the recognition mechanism of Stp1 in depth, we have determined a series of crystal structures of S. Read More

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http://pubs.acs.org/doi/10.1021/acsinfecdis.8b00316
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http://dx.doi.org/10.1021/acsinfecdis.8b00316DOI Listing
March 2019
2 Reads

IID572: A New Potentially Best-In-Class β-Lactamase Inhibitor.

ACS Infect Dis 2019 Mar 27. Epub 2019 Mar 27.

Novartis Institutes for BioMedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.

Resistance in Gram-negative bacteria to β-lactam drugs is mediated primarily by the expression of β-lactamases, and co-dosing of β-lactams with a β-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New β-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00031DOI Listing

Quantifying the Interactions between Biomolecules: Guidelines for Assay Design and Data Analysis.

Authors:
Peter J Tonge

ACS Infect Dis 2019 Apr 13. Epub 2019 Apr 13.

Center for Advanced Study of Drug Action, Departments of Chemistry and Radiology , Stony Brook University , John S. Toll Drive , Stony Brook , New York 11794-3400 , United States.

The accurate and precise determination of binding interactions plays a central role in fields such as drug discovery where structure-activity relationships guide the selection and optimization of drug leads. Binding is often assessed by monitoring the response caused by varying one of the binding partners in a functional assay or by using methods where the concentrations of free and/or bound ligand can be directly determined. In addition, there are also many approaches where binding leads to a change in the properties of the binding partner(s) that can be directly quantified such as an alteration in mass or in a spectroscopic signal. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00012DOI Listing

Multi-Omics Strategies Uncover Host-Pathogen Interactions.

ACS Infect Dis 2019 Apr 25;5(4):493-505. Epub 2019 Mar 25.

Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases , National Institutes of Health (NIH) , 9000 Rockville Pike , Bethesda , Maryland 20814 , United States.

With the success of the Human Genome Project, large-scale systemic projects became a reality that enabled rapid development of the systems biology field. Systems biology approaches to host-pathogen interactions have been instrumental in the discovery of some specifics of Gram-negative bacterial recognition, host signal transduction, and immune tolerance. However, further research, particularly using multi-omics approaches, is essential to untangle the genetic, immunologic, (post)transcriptional, (post)translational, and metabolic mechanisms underlying progression from infection to clearance of microbes. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00080DOI Listing
April 2019
2 Reads

5-Carboxytetramethylrhodamine-Ampicillin Fluorescence Anisotropy-Based Assay of Escherichia coli Penicillin-Binding Protein 2 Transpeptidase Inhibition.

ACS Infect Dis 2019 Mar 19. Epub 2019 Mar 19.

Entasis Therapeutics , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.

The high-molecular mass penicillin-binding proteins (PBPs) are the essential targets of the β-lactam classes of antibacterial drugs. In the Gram-negative pathogen Escherichia coli, these include PBP1a, PBP1b, PBP2, and PBP3. Techniques that enable facile measurement of the potency of inhibition of these targets are valuable for understanding structure-activity relationships in programs aimed at discovering new antibiotics to combat drug-resistant infections. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00351DOI Listing
March 2019
2 Reads

Zika Virus NS5 Forms Supramolecular Nuclear Bodies That Sequester Importin-α and Modulate the Host Immune and Pro-Inflammatory Response in Neuronal Cells.

ACS Infect Dis 2019 Mar 19. Epub 2019 Mar 19.

Program in Emerging Infectious Diseases , Duke-NUS Medical School , 8 College Road , Singapore 169857.

The Zika virus (ZIKV) epidemic in the Americas was alarming because of its link with microcephaly in neonates and Guillain-Barré syndrome in adults. The unusual pathologies induced by ZIKV infection and the knowledge that the flaviviral nonstructural protein 5 (NS5), the most conserved protein in the flavivirus proteome, can modulate the host immune response during ZIKV infection prompted us to investigate the subcellular localization of NS5 during ZIKV infection and explore its functional significance. A monopartite nuclear localization signal (NLS) sequence within ZIKV NS5 was predicted by the cNLS Mapper program, and we observed localization of ZIKV NS5 in the nucleus of infected cells by immunostaining with specific antibodies. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00373DOI Listing
March 2019
2 Reads

Novel Mercapto Propionamide Derivatives with Potent New Delhi Metallo-β-Lactamase-1 Inhibitory Activity and Low Toxicity.

ACS Infect Dis 2019 Mar 14. Epub 2019 Mar 14.

Department of Natural Products Chemistry , School of PharmacyFudan University , 826 Zhangheng Road , Shanghai 201203 , China.

The emergence and worldwide prevalence of New Delhi metallo-β-lactamase 1 (NDM-1) expressing Gram-negative bacteria with resistance against most β-lactam antibiotics pose a serious threat to human health. However, no NDM-1 inhibitors are clinically approved at present. Herein, based on the lead compound captopril, a series of compounds were designed, synthesized, and evaluated for NDM-1 inhibitory activities. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00366DOI Listing

Semisynthetic Analogues of Anhydrotetracycline as Inhibitors of Tetracycline Destructase Enzymes.

ACS Infect Dis 2019 Apr 5;5(4):618-633. Epub 2019 Mar 5.

The Edison Family Center for Genome Sciences & Systems Biology , Washington University School of Medicine , 4513 Clayton Ave. , Campus Box 8510, St. Louis , Missouri 63108 , United States.

The synthesis and biological evaluation of semisynthetic anhydrotetracycline analogues as small molecule inhibitors of tetracycline-inactivating enzymes are reported. Inhibitor potency was found to vary as a function of enzyme (major) and substrate-inhibitor pair (minor), and anhydrotetracycline analogue stability to enzymatic and nonenzymatic degradation in solution contributes to their ability to rescue tetracycline activity in whole cell Escherichia coli expressing tetracycline destructase enzymes. Taken collectively, these results provide the framework for the rational design of next-generation inhibitor libraries en route to a viable and proactive adjuvant approach to combat the enzymatic degradation of tetracycline antibiotics. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00349DOI Listing
April 2019
1 Read

Simple Method for Studying in Vitro Protein-Protein Interactions Based on Protein Complementation and Its Application in Drug Screening Targeting Bacterial Transcription.

ACS Infect Dis 2019 Apr 6;5(4):521-527. Epub 2019 Mar 6.

Department of Microbiology , The Chinese University of Hong Kong, Prince of Wales Hospital , 30-32 Ngan Shing Street , Shatin , Hong Kong.

Protein-protein interactions (PPIs) underpin essential cellular processes of all organisms and are increasingly considered as drug targets. A number of techniques have been established to study PPIs; however, development of a simple and cost-effective method for in vitro high throughput screening of PPI inhibitors is still in demand or desirable. We report herein a simple method based on protein complementation for the in vitro study of PPIs, as well as screening of inhibitors against the PPI of interest. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00020DOI Listing
April 2019
1 Read

Discovery and Characterization of 2-Nitro-5-(4-(phenylsulfonyl)piperazin-1-yl)- N-(pyridin-4-ylmethyl)anilines as Novel Inhibitors of the Aedes aegypti Kir1 ( AeKir1) Channel.

ACS Infect Dis 2019 Mar 15. Epub 2019 Mar 15.

Department of Anesthesiology , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States.

Mosquito-borne arboviral diseases such as Zika, dengue fever, and chikungunya are transmitted to humans by infected adult female Aedes aegypti mosquitoes and affect a large portion of the world's population. The Kir1 channel in Ae. aegypti ( AeKir1) is an important ion channel in the functioning of mosquito Malpighian (renal) tubules and one that can be manipulated in order to disrupt excretory functions in mosquitoes. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00368DOI Listing
March 2019
1 Read

Simplified Autoinducing Peptide Mimetics with Single-Nanomolar Activity Against the Staphylococcus aureus AgrC Quorum Sensing Receptor.

ACS Infect Dis 2019 Apr 13;5(4):484-492. Epub 2019 Mar 13.

Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , United States.

Staphylococcus aureus is a leading cause of hospital-acquired infections worldwide, and cases of community-acquired infections are becoming more prevalent. The production of numerous virulence factors in S. aureus is under the control of the accessory gene regulator (agr) quorum sensing (QS) system. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461479PMC

Combining 25-Hydroxycholesterol with an HIV Fusion Inhibitor Peptide: Interaction with Biomembrane Model Systems and Human Blood Cells.

ACS Infect Dis 2019 Apr 28;5(4):582-591. Epub 2019 Feb 28.

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Lisbon 1649-028 , Portugal.

The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00321DOI Listing
April 2019
1 Read

Evolved Proteins Inhibit Entry of Enfuvirtide-Resistant HIV-1.

ACS Infect Dis 2019 Apr 12;5(4):634-640. Epub 2019 Mar 12.

Department of Chemistry , Colorado State University , 200 W. Lake Street , Fort Collins , Colorado 80523 , United States.

Drugs that block HIV-1 entry are relatively limited. Enfuvirtide is a 36-residue synthetic peptide that targets gp41 and blocks viral fusion. However, Enfuvirtide-resistant HIV has been reported, and this peptide drug requires daily injection. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00362DOI Listing

Genetic, Biochemical, and Structural Characterization of CMY-136 β-Lactamase, a Peculiar CMY-2 Variant.

ACS Infect Dis 2019 Apr 7;5(4):528-538. Epub 2019 Mar 7.

EA7361 "Structure, dynamic, function and expression of broad spectrum β-lactamases" , Université Paris Sud, Université Paris Saclay, LabEx LERMIT, Faculty of Medicine , 78 rue du Général Leclerc , 94275 Le Kremlin-Bicêtre , France.

With the widespread use and abuse of antibiotics for the past decades, antimicrobial resistance poses a serious threat to public health nowadays. β-Lactams are the most used antibiotics, and β-lactamases are the most widespread resistance mechanism. Class C β-lactamases, also known as cephalosporinases, usually do not hydrolyze the latest and most potent β-lactams, expanded spectrum cephalosporins and carbapenems. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00240DOI Listing
April 2019
15 Reads

The Adaptive Proline Response in P. falciparum Is Independent of PfeIK1 and eIF2α Signaling.

ACS Infect Dis 2019 Apr 21;5(4):515-520. Epub 2019 Feb 21.

Harvard T.H. Chan School of Public Health , 665 Huntington Avenue , Boston , Massachusetts 02115 , United States.

We have previously identified the cytoplasmic prolyl tRNA synthetase in Plasmodium falciparum as the functional target of the natural product febrifugine and its synthetic analogue halofuginone (HFG), one of the most potent antimalarials discovered to date. However, our studies also discovered that short-term treatment of asexual blood stage P. falciparum with HFG analogues causes a 20-fold increase in intracellular proline, termed the adaptive proline response (APR), which renders parasites tolerant to HFG. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00363DOI Listing

Discovery of New Hepatitis B Virus Capsid Assembly Modulators by an Optimal High-Throughput Cell-Based Assay.

ACS Infect Dis 2019 Feb 22. Epub 2019 Feb 22.

School of Pharmaceutical Sciences , Tsinghua University , Renhuan Building, Room 311 , Beijing 100084 , China.

In this article, a simple and effective high-throughput screening (HTS) assay was developed to identify anti-HBV compounds by using a HepAD38 luciferase reporter (HepAD38-luc) cell line that can effectively exclude the false positive hit compounds targeted on the tetracycline off (tet-off) regulation system. Through screening in-house chemical libraries, N-phenylpiperidine-3-carboxamide derivatives, represented by 1 and 2, were identified, while the other false positive hits (i.e. Read More

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http://dx.doi.org/10.1021/acsinfecdis.9b00030DOI Listing
February 2019
2 Reads

Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase.

ACS Infect Dis 2019 Apr 28;5(4):570-581. Epub 2019 Feb 28.

VA Tennessee Valley Healthcare System , 1310 24th Avenue S. , Nashville , Tennessee 37212 , United States.

Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461504PMC
April 2019
1 Read

Targeted Inhibition of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 with a Constrained J Domain-Derived Disruptor Peptide.

ACS Infect Dis 2019 Apr 18;5(4):506-514. Epub 2019 Feb 18.

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy , University of Georgia , 240 W. Green Street , Athens , Georgia 30602 , United States.

To explore the possibility of constrained peptides to target Plasmodium-infected cells, we designed a J domain mimetic derived from Plasmodium falciparum calcium-dependent protein kinase 1 ( PfCDPK1) as a strategy to disrupt J domain binding and inhibit PfCDPK1 activity. The J domain disruptor (JDD) peptide was conformationally constrained using a hydrocarbon staple and was found to selectively permeate segmented schizonts and colocalize with intracellular merozoites in late-stage parasites. In vitro analyses demonstrated that JDD could effectively inhibit the catalytic activity of recombinant PfCDPK1 in the low micromolar range. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461495PMC
April 2019
3 Reads

Structure-Activity Relationship of Sulfonyl Piperazine LpxH Inhibitors Analyzed by an LpxE-Coupled Malachite Green Assay.

ACS Infect Dis 2019 Apr 5;5(4):641-651. Epub 2019 Feb 5.

Department of Chemistry , Duke University , 124 Science Drive , Box 90346, Durham , North Carolina 27708 , United States.

The UDP-2,3-diacylglucosamine pyrophosphatase LpxH in the Raetz pathway of lipid A biosynthesis is an essential enzyme in the vast majority of Gram-negative pathogens and an excellent novel antibiotic target. The P-radioautographic thin-layer chromatography assay has been widely used for analysis of LpxH activity, but it is inconvenient for evaluation of a large number of LpxH inhibitors over an extended time period. Here, we report a coupled, nonradioactive LpxH assay that utilizes the recently discovered Aquifex aeolicus lipid A 1-phosphatase LpxE for quantitative removal of the 1-phosphate from lipid X, the product of the LpxH catalysis; the released inorganic phosphate is subsequently quantified by the colorimetric malachite green assay, allowing the monitoring of the LpxH catalysis. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00364DOI Listing
April 2019
1 Read

Insight into the Effects of Plasmodium chabaudi on Platelets Using Carbon-Fiber Microelectrode Amperometry.

ACS Infect Dis 2019 Apr 15;5(4):592-597. Epub 2019 Feb 15.

Department of Chemistry , University of Minnesota , 207 Pleasant Street SE , Minneapolis , Minnesota 55455 , United States.

Platelets are anuclear circulating cell bodies within the bloodstream commonly known for their roles in clot formation during vascular injury to prevent blood loss. They also have significant impact in a range of diseases, including malaria. However, the role of platelets in malaria is controversial, with contradicting evidence suggesting either that they assist in destruction of malarial parasites or facilitate a severe form of malaria. Read More

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http://dx.doi.org/10.1021/acsinfecdis.8b00334DOI Listing