scholarly journals Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Adam D. Tomich ◽  
Erik H. Klontz ◽  
Daniel Deredge ◽  
John P. Barnard ◽  
Christi L. McElheny ◽  
...  
Keyword(s):  
Small Molecule ◽  
Multidrug Resistant ◽  
Public Health Issue ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Track Record ◽  
New Strategy ◽  
New Antibiotics ◽  
Resistant Strains

ABSTRACTThe spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active againstEscherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the “priority pathogens”Klebsiella pneumoniaeandPseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomalfosAgene, which directs expression of a metal-dependent glutathioneS-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one), a small-molecule active-site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.

scholarly journals Complete Genome Sequence of Klebsiella pneumoniae Myophage Magnus

2019 ◽  
Vol 8 (39) ◽  
Author(s):  
Laura E. Acevedo Ugarriza ◽  
Jordyn Michalik-Provasek ◽  
Heather Newkirk ◽  
Mei Liu ◽  
Jason J. Gill ◽  
...  
Keyword(s):  
Public Health ◽  
Klebsiella Pneumoniae ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Multidrug Resistant ◽  
Public Health Issue ◽  
Gram Negative ◽  
Content Type ◽  
Resistant Strains

Bacteriophage Magnus infects Klebsiella pneumoniae, a Gram-negative pathogen whose multidrug-resistant strains are a public health issue. Here, we describe the annotation of the 157,741-bp Magnus genome and its similarity to other myophages.

scholarly journals In VitroActivity of RX-P873 against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii

2015 ◽  
Vol 59 (4) ◽  
pp. 2280-2285 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Ronald N. Jones ◽  
David J. Farrell
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Active Agent ◽  
Multidrug Resistant ◽  
Surveillance Program ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Bacterial Ribosome

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.

scholarly journals In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Gregory G. Stone ◽  
Patricia A. Bradford ◽  
Margaret Tawadrous ◽  
Dianna Taylor ◽  
Mary Jane Cadatal ◽  
...  
Keyword(s):  
Nosocomial Pneumonia ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Ventilator Associated Pneumonia ◽  
Phase 3 ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

scholarly journals Synergistic Activity of Colistin-Containing Combinations against Colistin-ResistantEnterobacteriaceae

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Alejandro Pironti ◽  
James E. Kirby
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Bacterial Outer Membrane ◽  
Time Kill ◽  
Synergistic Combinations

ABSTRACTResistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistantEnterobacteriaceae(CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistantEnterobacteriaceaeisolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

scholarly journals Activity of Eravacycline against Escherichia coli Clinical Isolates Collected from U.S. Veterans in 2011 in Relation to Coresistance Phenotype and Sequence Type 131 Genotype

2015 ◽  
Vol 60 (3) ◽  
pp. 1888-1891 ◽  
Author(s):  
James R. Johnson ◽  
Stephen B. Porter ◽  
Brian D. Johnston ◽  
Paul Thuras
Keyword(s):  
Escherichia Coli ◽  
Multidrug Resistant ◽  
Veterans Affairs ◽  
Sequence Type ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Medical Centers ◽  
Resistant Strains ◽  
Veterans Affairs Medical Centers

Eravacycline is a novel broad-spectrum fluorocycline with potent Gram-negative activity, including for multidrug-resistant strains. Among 472Escherichia coliclinical isolates from 24 Veterans Affairs medical centers (in 2011), divided equally as susceptible versus resistant to fluoroquinolones, broth microdilution eravacycline MICs were distributed unimodally, ranging from 0.03 to 1.0 μg/ml (MIC50of 0.125 μg/ml, MIC90of 0.25 μg/ml). Eravacycline MICs were ∼2-fold higher among fluoroquinolone-resistant, gentamicin-resistant, multidrug-resistant, and sequence type 131 (ST131) isolates (P< 0.01 for each comparison).

The role of new antibiotics in intra-abdominal infections in the era of multi-resistant bacteria

2019 ◽  
Vol 98 (4) ◽  
pp. 145-151
Keyword(s):  
Multidrug Resistant ◽  
University Hospital ◽  
Resistant Bacteria ◽  
Highly Active ◽  
Carbapenem Resistant ◽  
New Antibiotics ◽  
Amoxicillin Clavulanic Acid ◽  
Resistant Strains ◽  
Lactam B ◽  
Abdominal Infections

Complicated intra-abdominal infections (cIAI) are a substantial cause of morbidity at intensive care units. cIAI are frequently caused by multidrug- resistant strains of Enterobacteriaceae and Pseudomonas aeruginosa. In 592 cIAI patients from the First Department of Surgery, General University Hospital in Prague, we found an alarming increase in resistance of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam and third-generation cephalosporins in 2014–2017 (from 28.7% in 2014 to 37.5% in 2017, from 25% to 32% and from 2.3% to 5.6%, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam are novel cephalosporins available for the treatment of cIAI. Ceftolozane/tazobactam is highly active against multidrug-resistant strains of P. aeruginosa, including carbapenem-resistant isolates. The new non-b-lactam b-lactamase inhibitor avibactam plus ceftazidime is active against carbapenemases-producing strains of Enterobacteriaceae. Both antibiotics are included in the new WSES guidelines for the management of cIAI.

scholarly journals Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of PlasmodiumIn VivoandIn Vitro

2012 ◽  
Vol 56 (9) ◽  
pp. 4685-4692 ◽  
Author(s):  
Fabián E. Sáenz ◽  
Tina Mutka ◽  
Kenneth Udenze ◽  
Ayoade M. J. Oduola ◽  
Dennis E. Kyle
Keyword(s):  
Plasmodium Berghei ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Content Type ◽  
Highly Active ◽  
Resistant Strains ◽  
Sexual Stages ◽  
The 1960S

ABSTRACTNew drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s,Plasmodium falciparumresistance to this drug has spread globally, and more recently, emerging resistance to CQ byPlasmodium vivaxthreatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845,N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846,N1-(7-chloro-quinolin-4-yl)-2,N2,N2-trimethylpropane-1,2-diamine and found them to be active againstP. falciparumin vitroandPlasmodium bergheiin vivo. TheP. falciparumclones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC50s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4-aminoquinolines were active against early and lateP. falciparumgametocyte stages and cured BALB/c mice infected withP. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistantP. falciparumandP. vivax.

scholarly journals Disrupting Gram-Negative Bacterial Outer Membrane Biosynthesis through Inhibition of the Lipopolysaccharide Transporter MsbA

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Mary Kate Alexander ◽  
Anh Miu ◽  
Angela Oh ◽  
Mike Reichelt ◽  
Hoangdung Ho ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Drug Targets ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Transport Pathway ◽  
Gram Negative ◽  
Content Type ◽  
Outer Leaflet ◽  
New Antibiotics ◽  
Outer Membrane Biogenesis

ABSTRACTThere is a critical need for new antibacterial strategies to counter the growing problem of antibiotic resistance. In Gram-negative bacteria, the outer membrane (OM) provides a protective barrier against antibiotics and other environmental insults. The outer leaflet of the outer membrane is primarily composed of lipopolysaccharide (LPS). Outer membrane biogenesis presents many potentially compelling drug targets as this pathway is absent in higher eukaryotes. Most proteins involved in LPS biosynthesis and transport are essential; however, few compounds have been identified that inhibit these proteins. The inner membrane ABC transporter MsbA carries out the first essential step in the trafficking of LPS to the outer membrane. We conducted a biochemical screen for inhibitors of MsbA and identified a series of quinoline compounds that killEscherichia colithrough inhibition of its ATPase and transport activity, with no loss of activity against clinical multidrug-resistant strains. Identification of these selective inhibitors indicates that MsbA is a viable target for new antibiotics, and the compounds we identified serve as useful tools to further probe the LPS transport pathway in Gram-negative bacteria.

scholarly journals In VivoEfficacy of Glycopeptide-Colistin Combination Therapies in aGalleria mellonellaModel ofAcinetobacter baumanniiInfection

2011 ◽  
Vol 55 (7) ◽  
pp. 3534-3537 ◽  
Author(s):  
M. Hornsey ◽  
D. W. Wareham
Keyword(s):  
Galleria Mellonella ◽  
Survival Rates ◽  
Multidrug Resistant ◽  
New Agents ◽  
Content Type ◽  
Highly Active ◽  
Resistant Strains ◽  
Immunomodulatory Action ◽  
Lethal Doses

ABSTRACTThe treatment ofAcinetobacter baumanniiinfections poses a significant clinical challenge, with isolates resistant to all commonly used agents increasingly being reported. With few new agents in the pipeline, clinicians are increasingly turning to combinations of antimicrobials in the hope that they may act synergistically together. In this study we assessed the activities of two glycopeptide-colistin combinations bothin vitroand using aGalleria mellonellacaterpillar model ofA. baumanniiinfection. In checkerboard assays both vancomycin and teicoplanin were highly active against susceptible and multidrug-resistant strains ofA. baumanniiwhen combined with colistin (fractional inhibitory concentration [FIC] of <0.25). Treatment ofG. mellonellacaterpillars infected with lethal doses ofA. baumanniiresulted in significantly enhanced survival rates when either vancomycin or teicoplanin was given with colistin compared to colistin treatment alone (P< 0.05). This effect was most marked when vancomycin was the glycopeptide administered, although this agent was also highly effective as monotherapy, possibly through an immunomodulatory action on theG. mellonellaresponse toA. baumanniiinfection. This work suggests that glycopeptide-colistin combinations are highly active againstA. baumanniibothin vitroand in a simple animal model of infection. They should be considered further as potential treatments for difficult-to-treatA. baumanniiinfections.

scholarly journals Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria

2016 ◽  
Vol 60 (5) ◽  
pp. 3215-3218 ◽  
Author(s):  
Wentao Ni ◽  
Yanjun Li ◽  
Jie Guan ◽  
Jin Zhao ◽  
Junchang Cui ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Content Type ◽  
Resistant Strains ◽  
Efflux Pump Inhibitors ◽  
Time Kill

ABSTRACTWe tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially inAcinetobacter baumanniiandStenotrophomonas maltophilia. These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP.

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