当前位置： SCI文献检索 > ACS Infectious Diseases期刊下所有文献 > Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus.

Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus.

Abstract：

:The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural, and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMP resistant (TMPR) and methicillin resistant Staphylococcus aureus (MRSA) isolates.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Reeve SM,Si D,Krucinska J,Yan Y,Viswanathan K,Wang S,Holt GT,Frenkel MS,Ojewole AA,Estrada A,Agabiti SS,Alverson JB,Gibson ND,Priestley ND,Wiemer AJ,Donald BR,Wright DL

doi

10.1021/acsinfecdis.9b00222

subject

Has Abstract

pub_date

2019-11-08 00:00:00

pages

1896-1906

issue

11

issn

2373-8227

journal_volume

5

pub_type

杂志文章

相关文献

ACS Infectious Diseases文献大全
  • Inhibition of Marburg Virus RNA Synthesis by a Synthetic Anti-VP35 Antibody.

    abstract：:Marburg virus causes sporadic outbreaks of severe hemorrhagic fever with high case fatality rates. Approved, effective, and safe therapeutic or prophylactic countermeasures are lacking. To address this, we used phage display to engineer a synthetic antibody, sFab H3, which binds the Marburg virus VP35 protein (mVP35)....

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.9b00091

    authors： Amatya P,Wagner N,Chen G,Luthra P,Shi L,Borek D,Pavlenco A,Rohrs H,Basler CF,Sidhu SS,Gross ML,Leung DW

    更新日期：2019-08-09 00:00:00

  • Immunoassay for HIV Drug Metabolites Tenofovir and Tenofovir Diphosphate.

    abstract：:Poor patient adherence to antiretroviral medication represents a major obstacle for managing disease and reducing rates of new HIV infections. The measurement of patient drug levels is the most objective method of determining adherence. Tenofovir and tenofovir diphosphate are metabolites of some of the most common HIV...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00010

    authors： Sevenler D,Bardon A,Fernandez Suarez M,Marshall L,Toner M,Drain PK,Sandlin RD

    更新日期：2020-07-10 00:00:00

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

    abstract：: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 bac...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00268

    authors： Martínez SR,Ibarra LE,Ponzio RA,Forcone MV,Wendel AB,Chesta CA,Spesia MB,Palacios RE

    更新日期：2020-08-14 00:00:00

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

    abstract：: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...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00243

    authors： Torralba J,de la Arada I,Carravilla P,Insausti S,Rujas E,Largo E,Eggeling C,Arrondo JLR,Apellániz B,Nieva JL

    更新日期：2020-08-14 00:00:00

  • Mechanistic Evaluation of Lipopolysaccharide-Alexidine Interaction Using Spectroscopic and in Silico Approaches.

    abstract：:The increasing problem of multidrug resistance (MDR) in bacteria calls for discovery of new molecules and diagnostic methodologies that are effective against a wide range of microbial pathogens. We have studied the role of alexidine dihydrochloride (alex) as a bioaffinity ligand against lipopolysaccharide (LPS), a pat...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00087

    authors： Jagtap P,Mishra R,Khanna S,Kumari P,Mittal B,Kashyap HK,Gupta S

    更新日期：2018-11-09 00:00:00

  • LRRK2 in Infection: Friend or Foe?

    abstract：: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 p...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.9b00051

    authors： Herbst S,Gutierrez MG

    更新日期：2019-06-14 00:00:00

  • High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria.

    abstract：:In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening metho...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.5b00143

    authors： Swann J,Corey V,Scherer CA,Kato N,Comer E,Maetani M,Antonova-Koch Y,Reimer C,Gagaring K,Ibanez M,Plouffe D,Zeeman AM,Kocken CH,McNamara CW,Schreiber SL,Campo B,Winzeler EA,Meister S

    更新日期：2016-04-08 00:00:00

  • A Comparison of Optical, Electrochemical, Magnetic, and Colorimetric Point-of-Care Biosensors for Infectious Disease Diagnosis.

    abstract：:Each year, infectious diseases are responsible for millions of deaths, most of which occur in the rural areas of developing countries. Many of the infectious disease diagnostic tools used today require a great deal of time, a laboratory setting, and trained personnel. Due to this, the need for effective point-of-care ...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.8b00023

    authors： Pashchenko O,Shelby T,Banerjee T,Santra S

    更新日期：2018-08-10 00:00:00

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

    abstract：: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. coli clamp binding pocket, EcS346 a...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.9b00089

    authors： André C,Martiel I,Wolff P,Landolfo M,Lorber B,Silva da Veiga C,Dejaegere A,Dumas P,Guichard G,Oliéric V,Wagner J,Burnouf DY

    更新日期：2019-06-14 00:00:00

  • Synergistic Effect of Combined Artesunate and Tetramethylpyrazine in Experimental Cerebral Malaria.

    abstract：:Intravenous artesunate is effective against cerebral malaria (CM), but high mortality and neurological sequelae in survivors are inevitable. We investigated the effect of combined artesunate and tetramethylpyrazine using mouse models of experimental cerebral malaria (ECM). Artesunate + tetramethylpyrazine reduced micr...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00124

    authors： Jiang X,Chen L,Zheng Z,Chen Y,Weng X,Guo Y,Li K,Yang T,Qu S,Liu H,Li Y,Zhu X

    更新日期：2020-09-11 00:00:00

  • Porphyromonas gingivalis Infection Promoted the Proliferation of Oral Squamous Cell Carcinoma Cells through the miR-21/PDCD4/AP-1 Negative Signaling Pathway.

    abstract：:Recent epidemiological studies have revealed that Porphyromonas gingivalis, a major pathogen in periodontal disease, is associated with the development of oral squamous cell carcinoma (OSCC). However, the underlying mechanisms induced by P. gingivalis have not been well-defined. We aimed to determine the role of P. gi...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.9b00032

    authors： Chang C,Wang H,Liu J,Pan C,Zhang D,Li X,Pan Y

    更新日期：2019-08-09 00:00:00

  • Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization.

    abstract：:Because of its essential role as a bacterial virulence factor, enzyme sortase A (SrtA) has become an attractive target for the development of new antivirulence drugs against Gram-positive infections. Here we describe 27 compounds identified as covalent inhibitors of Staphylococcus aureus SrtA by screening a library of...

    journal_title：ACS infectious diseases

    pub_type： 信件

    doi：10.1021/acsinfecdis.9b00265

    authors： Jaudzems K,Kurbatska V,Je Kabsons A,Bobrovs R,Rudevica Z,Leonchiks A

    更新日期：2020-02-14 00:00:00

  • Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery.

    abstract：:Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug de...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.7b00276

    authors： Luth MR,Gupta P,Ottilie S,Winzeler EA

    更新日期：2018-03-09 00:00:00

  • Enterovirus D68 Antivirals: Past, Present, and Future.

    abstract：:Enterovirus D68 (EV-D68) is an RNA virus that causes respiratory illnesses mainly in children. In severe cases, it can lead to neurological complications such as acute flaccid myelitis (AFM). EV-D68 belongs to the enterovirus genera of the Picornaviridae family, which also includes many other significant human pathoge...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00120

    authors： Hu Y,Musharrafieh R,Zheng M,Wang J

    更新日期：2020-07-10 00:00:00

  • Overcoming an Extremely Drug Resistant (XDR) Pathogen: Avibactam Restores Susceptibility to Ceftazidime for Burkholderia cepacia Complex Isolates from Cystic Fibrosis Patients.

    abstract：:Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different ...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.7b00020

    authors： Papp-Wallace KM,Becka SA,Zeiser ET,Ohuchi N,Mojica MF,Gatta JA,Falleni M,Tosi D,Borghi E,Winkler ML,Wilson BM,LiPuma JJ,Nukaga M,Bonomo RA

    更新日期：2017-07-14 00:00:00

  • Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

    abstract：:Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increas...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00322

    authors： Li PC,Jang J,Hsia CY,Groomes PV,Lian W,de Wispelaere M,Pitts JD,Wang J,Kwiatkowski N,Gray NS,Yang PL

    更新日期：2019-03-08 00:00:00

  • Toward Curative Immunomodulation Strategies for Chronic Hepatitis B Virus Infection.

    abstract：: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 th...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.8b00297

    authors： Zhu W,Liu H,Zhang X

    更新日期：2019-05-10 00:00:00

  • Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens.

    abstract：:Superoxide anion radical is generated as a natural byproduct of aerobic metabolism but is also produced as part of the oxidative burst of the innate immune response design to kill pathogens. In living systems, superoxide is largely managed through superoxide dismutases (SODs), families of metalloenzymes that use Fe, M...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.8b00026

    authors： Schatzman SS,Culotta VC

    更新日期：2018-06-08 00:00:00

  • Instructive Advances in Chemical Microbiology Inspired by Nature's Diverse Inventory of Molecules.

    abstract：:Natural product antibiotics have played an essential role in the treatment of bacterial infection in addition to serving as useful tools to explore the intricate biology of bacteria. Our current arsenal of antibiotics operate through the inhibition of well-defined bacterial targets critical for replication and growth....

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.9b00413

    authors： Liu K,Huigens RW 3rd

    更新日期：2020-04-10 00:00:00

  • Staphylococcus aureus Specific FRET Probe-Based Antibacterial Susceptibility Testing (SF-AST) by Detection of Micrococcal Nuclease Activity.

    abstract：:In this study, we describe a simple and rapid antibacterial susceptibility testing (AST) method for Staphylococcus aureus called S. aureus specific fluorescence resonance energy transfer (FRET) probe-based AST (SF-AST), which is based on an S. aureus specific FRET probe (SF probe) that detects micrococcal nuclease (MN...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.9b00260

    authors： Yi SY,Jeong J,Kim KE,Park K,Shin YB

    更新日期：2020-02-14 00:00:00

  • An "Unlikely" Pair: The Antimicrobial Synergy of Polymyxin B in Combination with the Cystic Fibrosis Transmembrane Conductance Regulator Drugs KALYDECO and ORKAMBI.

    abstract：:Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gr...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.6b00035

    authors： Schneider EK,Azad MA,Han ML,Tony Zhou Q,Wang J,Huang JX,Cooper MA,Doi Y,Baker MA,Bergen PJ,Muller MT,Li J,Velkov T

    更新日期：2016-07-08 00:00:00

  • Investigational Studies on a Hit Compound Cyclopropane-Carboxylic Acid Derivative Targeting O-Acetylserine Sulfhydrylase as a Colistin Adjuvant.

    abstract：:Antibacterial adjuvants are of great significance, since they allow the therapeutic dose of conventional antibiotics to be lowered and reduce the insurgence of antibiotic resistance. Herein, we report that an O-acetylserine sulfhydrylase (OASS) inhibitor can be used as a colistin adjuvant to treat infections caused by...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.0c00378

    authors： Annunziato G,Spadini C,Franko N,Storici P,Demitri N,Pieroni M,Flisi S,Rosati L,Iannarelli M,Marchetti M,Magalhaes J,Bettati S,Mozzarelli A,Cabassi CS,Campanini B,Costantino G

    更新日期：2021-01-29 00:00:00

  • Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa.

    abstract：:Understanding molecular properties of outer membrane channels of Gram-negative bacteria is of fundamental significance as they are the entry point of polar antibiotics into bacteria. Outer membrane proteomics revealed OccK8 (OprE) to be among the five most expressed substrate specific channels of the clinically import...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00149

    authors： Samanta S,Bodrenko I,Acosta-Gutiérrez S,D'Agostino T,Pathania M,Ghai I,Schleberger C,Bumann D,Wagner R,Winterhalter M,van den Berg B,Ceccarelli M

    更新日期：2018-10-12 00:00:00

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

    abstract：: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 (M...

    journal_title：ACS infectious diseases

    pub_type： 历史文章,杂志文章,评审

    doi：10.1021/acsinfecdis.0c00291

    authors： Oldfield E,Malwal SR

    更新日期：2020-07-10 00:00:00

  • Detection of Bacterial Coinfection in COVID-19 Patients Is a Missing Piece of the Puzzle in the COVID-19 Management in Indonesia.

    abstract：:Bacterial coinfection in COVID-19 patients has the potential to complicate treatments and accelerate the development of antibiotic resistance in the clinic due to the widespread use of broad-spectrum antibiotics, including in Indonesia. The surge of COVID-19 patients may worsen antibiotic overuse; therefore, informati...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.1c00006

    authors： Prasetyoputri A

    更新日期：2021-01-27 00:00:00

  • Fitness Landscape of the Immune Compromised Favors the Emergence of Antibiotic Resistance.

    abstract：:Antibiotic resistance can come at a high cost, both in terms of fitness for the pathogen and poorer outcomes for patients. The fitness landscape encountered by bacterial pathogens varies greatly throughout patient populations in terms of host immunity as well as the duration and spectrum of antibiotics encountered. Se...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00158

    authors： Margolis E,Rosch JW

    更新日期：2018-09-14 00:00:00

  • Biogenic and Biomimetic Carriers as Versatile Transporters To Treat Infections.

    abstract：:Biogenic and biomimetic therapeutics are a relatively new class of systems that are of physiological origin and/or take advantage of natural pathways or aim at mimicking these to improve selective interaction with target tissue. The number of biogenic and bioengineered avenues for drug therapy and diagnostics has mult...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章,评审

    doi：10.1021/acsinfecdis.8b00030

    authors： Goes A,Fuhrmann G

    更新日期：2018-06-08 00:00:00

  • Daptomycin Leakage Is Selective.

    abstract：:Daptomycin is a lipopeptide antibiotic approved for use against Gram-positive organisms, including highly resistant species. A number of studies have suggested that daptomycin kills bacteria by membrane permeabilization and depolarization. Recently a model membrane system consisting of 1,2-dimyristoyl-sn-glycero-3-pho...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.6b00152

    authors： Zhang J,Scoten K,Straus SK

    更新日期：2016-10-14 00:00:00

  • Structure-Activity Relationships of the Competence Stimulating Peptide in Streptococcus mutans Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation.

    abstract：:Streptococcus mutans ( S. mutans) is a Gram-positive human pathogen that is one of the major contributors to dental caries, a condition with an economic cost of over $100 billion per year in the United States. S. mutans secretes a 21-amino-acid peptide termed the competence stimulating peptide (21-CSP) to assess its p...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00115

    authors： Bikash CR,Hamry SR,Tal-Gan Y

    更新日期：2018-09-14 00:00:00

  • A Computationally Designed Peptide Derived from Escherichia coli as a Potential Drug Template for Antibacterial and Antibiofilm Therapies.

    abstract：:Computer-aided screening of antimicrobial peptides (AMPs) is a promising approach for discovering novel therapies against multidrug-resistant bacterial infections. Here, we functionally and structurally characterized an Escherichia coli-derived AMP (EcDBS1R5) previously designed through pattern identification [α-helic...

    journal_title：ACS infectious diseases

    pub_type： 杂志文章

    doi：10.1021/acsinfecdis.8b00219

    authors： Cardoso MH,Cândido ES,Chan LY,Der Torossian Torres M,Oshiro KGN,Rezende SB,Porto WF,Lu TK,de la Fuente-Nunez C,Craik DJ,Franco OL

    更新日期：2018-12-14 00:00:00