scholarly journals The MUT056399 Inhibitor of FabI Is a New Antistaphylococcal Compound

2011 ◽  
Vol 55 (10) ◽  
pp. 4692-4697 ◽  
Author(s):  
S. Escaich ◽  
L. Prouvensier ◽  
M. Saccomani ◽  
L. Durant ◽  
M. Oxoby ◽  
...  
Keyword(s):  
Low Frequency ◽  
Systemic Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Immunocompetent Mice ◽  
Novel Drug

ABSTRACTMUT056399 is a highly potent new inhibitor of the FabI enzyme of bothStaphylococcus aureusandEscherichia coli. In vitro, MUT056399 was very active againstS. aureusstrains, including methicillin-susceptibleS. aureus(MSSA), methicillin-resistantS. aureus(MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC90s between 0.03 and 0.12 μg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC90s between 0.12 and 4 μg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli.In vitro, resistant clones ofS. aureuswere obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in thefabIgene.In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediateS. aureusstrains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections.

scholarly journals A Novel Ketolide, RBx 14255, with Activity against Multidrug-Resistant Streptococcus pneumoniae

2014 ◽  
Vol 58 (8) ◽  
pp. 4283-4289 ◽  
Author(s):  
V. Samuel Raj ◽  
Tarani Kanta Barman ◽  
Vandana Kalia ◽  
Kedar Purnapatre ◽  
Smita Dube ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pulmonary Infection ◽  
Systemic Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
The Novel ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTWe present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for itsin vitroandin vivoactivities against sensitive and macrolide-resistantStreptococcus pneumoniae. RBx 14255 showed excellentin vitroactivity against macrolide-resistantS. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistantS. pneumoniae3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. Thein vivoefficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation ofS. pneumoniaeATCC 6303 and systemic infection withS. pneumoniae3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 againstS. pneumoniaeATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistantS. pneumoniae3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

scholarly journals Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Sean M. Stainton ◽  
Kamilia Abdelraouf ◽  
Luke Utley ◽  
Michael J. Pucci ◽  
Troy Lister ◽  
...  
Keyword(s):  
Potential Role ◽  
Wide Spectrum ◽  
Structural Similarity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
Novel Agent

ABSTRACT SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

scholarly journals YraP Contributes to Cell Envelope Integrity and Virulence ofSalmonella entericaSerovar Typhimurium

2018 ◽  
Vol 86 (11) ◽  
Author(s):  
Faye C. Morris ◽  
Timothy J. Wells ◽  
Jack A. Bryant ◽  
Anna E. Schager ◽  
Yanina R. Sevastsyanovich ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cell Envelope ◽  
Systemic Infection ◽  
Eukaryotic Cell ◽  
Infection Model ◽  
Content Type ◽  
Protein Levels ◽  
K 12

ABSTRACTMutations in σE-regulated lipoproteins have previously been shown to impact bacterial viability under conditions of stress and duringin vivoinfection. YraP is conserved across a number of Gram-negative pathogens, includingNeisseria meningitidis, where the homolog is a component of the Bexsero meningococcal group B vaccine. Investigations using laboratory-adaptedEscherichia coliK-12 have shown thatyraPmutants have elevated sensitivity to a range of compounds, including detergents and normally ineffective antibiotics. In this study, we investigate the role of the outer membrane lipoprotein YraP in the pathogenesis ofSalmonella entericaserovar Typhimurium. We show that mutations inS. TyphimuriumyraPresult in a defective outer membrane barrier with elevated sensitivity to a range of compounds. This defect is associated with attenuated virulence in an oral infection model and during the early stages of systemic infection. We show that this attenuation is not a result of defects in lipopolysaccharide and O-antigen synthesis, changes in outer membrane protein levels, or the ability to adhere to and invade eukaryotic cell linesin vitro.

scholarly journals Therapeutic Effect and Mechanisms of the Novel Monosulfactam 0073

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Ying Sun ◽  
Xueyuan Liao ◽  
Zhigang Huang ◽  
Yaliu Xie ◽  
Yanbin Liu ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Serial Passage ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Infection Model ◽  
The Novel ◽  
Gram Negative ◽  
Content Type

ABSTRACT This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria in vitro and in vivo and to characterize the mechanisms underlying 0073 activity. The in vitro activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define in vivo efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC50), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both in vitro and in vivo. In the murine thigh infection model and the pneumonia models in which infection was induced by P. aeruginosa and Klebsiella pneumoniae, 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both in vitro and in vivo. The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.

scholarly journals The Novel β-Lactam Enhancer Zidebactam Augments theIn VivoPharmacodynamic Activity of Cefepime in a Neutropenic Mouse LungAcinetobacter baumanniiInfection Model

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
S. S. Bhagwat ◽  
H. Periasamy ◽  
S. S. Takalkar ◽  
S. R. Palwe ◽  
H. N. Khande ◽  
...  
Keyword(s):  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Mouse Lung ◽  
Infection Model ◽  
Bactericidal Action ◽  
Content Type ◽  
Time Kill ◽  
The Impact

ABSTRACTWCK 5222 is a combination of cefepime and the high-affinity PBP2-binding β-lactam enhancer zidebactam. The cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including carbapenemase-expressingAcinetobacter baumannii. The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition, leading to the enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of the zidebactam-mediated enhancedin vitrobactericidal action in modulating the percentage of the time that the free drug concentration remains above the MIC (percentfT>MIC) for cefepime required for thein vivokilling ofA. baumannii. Cefepime and cefepime-zidebactam MICs were comparable and ranged from 2 to 16 mg/liter for theA. baumanniistrains (n = 5) employed in the study. Time-kill studies revealed the improved killing of these strains by the cefepime-zidebactam combination compared to that by the constituents alone. Employing a neutropenic mouse lung infection model, exposure-response analyses for all theA. baumanniistrains showed that the cefepimefT>MIC required for 1-log10kill was 38.9%. In the presence of a noneffective dose of zidebactam, the cefepimefT>MIC requirement dropped significantly to 15.5%, but it still rendered a 1-log10kill effect. Thus, zidebactam mediated the improvement in cefepime’s bactericidal effect observed in time-kill studies, manifestedin vivothrough the lowering of cefepime’s pharmacodynamic requirement. This is a first-ever study demonstrating a β-lactam enhancer role of zidebactam that helps augment thein vivoactivity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures againstA. baumannii.

scholarly journals Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
David P. Nicolau
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Diverse Population ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Efficacy of Humanized Carbapenem Exposures against New Delhi Metallo-β-Lactamase (NDM-1)-Producing Enterobacteriaceae in a Murine Infection Model

2013 ◽  
Vol 57 (8) ◽  
pp. 3936-3940 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Patrice Nordmann ◽  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Maximal Activity ◽  
Bacterial Density ◽  
Infection Model ◽  
High Dose ◽  
New Delhi ◽  
Wild Type ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTEnterobacteriaceaeproducing the novel carbapenemase New Delhi metallo-β-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels ofin vitroresistance to multiple antibiotics,in vivoefficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-typeK. pneumoniaeand its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed thein vitromaintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was ≤8 μg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producingEnterobacteriaceaeunder certain conditions, and this warrants furtherin vivoexploration.

scholarly journals In VivoActivities of Simulated Human Doses of Cefepime and Cefepime-AAI101 against Multidrug-Resistant Gram-Negative Enterobacteriaceae

2015 ◽  
Vol 59 (5) ◽  
pp. 2688-2694 ◽  
Author(s):  
Jared L. Crandon ◽  
David P. Nicolau
Keyword(s):  
Multidrug Resistant ◽  
Time Profile ◽  
Free Drug ◽  
Bacterial Density ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Drug Concentrations

ABSTRACTThe combination of cefepime with AAI101, a novel extended-spectrum β-lactamase inhibitor, possesses potentin vitroactivity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the familyEnterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and thein vivoefficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10CFU (mean ± standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of ≥64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of ≥0.5 log10CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive ofin vivoactivity for the studied regimen.

scholarly journals In Vivo Characterization of the Peptide Deformylase Inhibitor LBM415 in Murine Infection Models

2009 ◽  
Vol 53 (9) ◽  
pp. 3777-3781 ◽  
Author(s):  
Colin S. Osborne ◽  
Georg Neckermann ◽  
Evelin Fischer ◽  
Robert Pecanka ◽  
Donghui Yu ◽  
...  
Keyword(s):  
Systemic Infection ◽  
Multidrug Resistant ◽  
Peptide Deformylase ◽  
Infection Model ◽  
In Vivo Efficacy ◽  
Infection Models ◽  
Specific Organ ◽  
In Vivo Characterization

ABSTRACT LBM415 is an antibacterial agent belonging to the peptide deformylase inhibitor class of compounds. It has previously been shown to demonstrate good activity in vitro against a range of pathogens. In this study, the in vivo efficacy of LBM415 was evaluated in various mouse infection models. We investigated activity against a systemic infection model caused by intraperitoneal inoculation of Staphylococcus aureus (methicillin [meticillin] susceptible [MSSA] and methicillin resistant [MRSA]) and Streptococcus pneumoniae (penicillin susceptible [PSSP] and multidrug resistant [MDRSP]), a thigh infection model caused by intramuscular injection of MRSA, and a lung infection produced by intranasal inoculation of PSSP. In the systemic MSSA and MRSA infections, LBM415 was equivalent to linezolid and vancomycin. In the systemic PSSP infection, LBM415 was equivalent to linezolid, whereas against systemic MDRSP infection, the LBM415 50% effective dose (ED50) was 4.8 mg/kg (dosed subcutaneously) and 36.6 mg/kg (dosed orally), compared to 13.2 mg/kg for telithromycin and >60 mg/kg for penicillin V and clarithromycin. In the MRSA thigh infection, LBM415 significantly reduced thigh bacterial levels compared to those of untreated mice, with levels similar to those after treatment with linezolid at the same dose levels. In the pneumonia model, the ED50 to reduce the bacterial lung burden by >4 log10 in 50% of treated animals was 23.3 mg/kg for LBM415, whereas moxifloxacin showed an ED50 of 14.3 mg/kg. In summary, LBM415 showed in vivo efficacy in sepsis and specific organ infection models irrespective of resistance to other antibiotics. Results suggest the potential of peptide deformylase inhibitors as a novel class of therapeutic agents against antibiotic-resistant pathogens.

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