scholarly journals Drug Repurposing: In vitro and in vivo Antimicrobial and Antibiofilm Effects of Bithionol Against Enterococcus faecalis and Enterococcus faecium

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengfei She ◽  
Yangxia Wang ◽  
Yingjia Li ◽  
Linying Zhou ◽  
Shijia Li ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Bacterial Load ◽  
Drug Repurposing ◽  
Infection Model ◽  
Dependent Manner ◽  
Antibiotic Development ◽  
Vancomycin Resistant ◽  
Conventional Antibiotics

Widespread antibiotic resistance has been reported in enterococcal pathogens that cause life-threatening infections. Enterococci species rapidly acquire resistance and the pace of new antibiotic development is slow. Drug repurposing is a promising approach in solving this problem. Bithionol (BT) is a clinically approved anthelminthic drug. In this study, we found that BT showed significant antimicrobial and antibiofilm effects against Enterococcus faecalis and vancomycin-resistant Entercococcus faecium in vitro, in a dose-dependent manner, by disrupting the integrity of the bacterial cell membranes. Moreover, BT effectively reduced the bacterial load in mouse organs when combined with conventional antibiotics in a peritonitis infection model. Thus, BT has shown potential as a therapeutic agent against E. faecalis- and vancomycin-resistant E. faecium-related infections.

scholarly journals Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

2005 ◽  
Vol 49 (6) ◽  
pp. 2294-2301 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
Christine M. Johnson ◽  
Diane K. Driscoll ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Significant Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Long Term Treatment

ABSTRACT This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

scholarly journals ThiL is a valid antibacterial target that is essential for both thiamine biosynthesis and salvage pathway in Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Hyung Jun Kim ◽  
Hyunjung Lee ◽  
Yunmi Lee ◽  
Inhee Choi ◽  
Yoonae Ko ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Target ◽  
Bacterial Load ◽  
Thiamine Pyrophosphate ◽  
Infection Model ◽  
Antibiotic Development ◽  
New Drug ◽  
Thiamine Biosynthesis

ABSTRACTThiamine pyrophosphate (TPP) is an essential cofactor for various pivotal cellular processes in all living organisms, including bacteria. As thiamine biosynthesis occurs in bacteria but not humans, bacterial thiamine biosynthesis is an attractive target for antibiotic development. Among enzymes in the thiamine biosynthetic pathway, thiamine monophosphate kinase (ThiL) catalyzes the final step of the pathway, phosphorylating thiamine monophosphate (TMP) to produce TPP. In this work, we extensively investigated ThiL in Pseudomonas aeruginosa, a major pathogen of hospital-acquired infections. We demonstrated that thiL deletion abolishes not only thiamine biosynthesis but also thiamine salvage capability, showing growth defects of the ΔthiL mutant even in the presence of thiamine derivatives except TPP. Most importantly, the pathogenesis of the ΔthiL mutant was markedly attenuated compared to wild-type bacteria, with lower inflammatory cytokine induction and 103~104 times decreased bacterial load in an in vivo infection model where the intracellular TPP level is in the submicromolar range. In order to validate P. aeruginosa ThiL (PaThiL) as a new drug target, we further characterized its biochemical properties determining a Vmax of 4.0±0.2 nomol·min−1 and KM values of 111±8 and 8.0±3.5μM for ATP and TMP, respectively. A subsequent in vitro small molecule screening identified PaThiL inhibitors including WAY213613 that is a noncompetitive inhibitor with a Ki value of 13.4±2.3 μM and a potential antibacterial activity against P. aeruginosa. This study proved that PaThiL is a new drug target against P. aeruginosa providing comprehensive biological and biochemical data that could facilitate to develop a new repertoire of antibiotics.

scholarly journals Staphylococcus aureus internalization impairs osteoblastic activity and early differentiation process

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
W. Mouton ◽  
J. Josse ◽  
C. Jacqueline ◽  
L. Abad ◽  
S. Trouillet-Assant ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Post Infection ◽  
Infection Model ◽  
Dependent Manner ◽  
Differentiation Process ◽  
Osteoblastic Activity ◽  
Bone Parameters ◽  
Early Differentiation

AbstractStaphylococcus aureus is the most frequent aetiology of bone and joint infections (BJI) and can cause relapsing and chronic infections. One of the main factors involved in the chronicization of staphylococcal BJIs is the internalization of S. aureus into osteoblasts, the bone-forming cells. Previous studies have shown that S. aureus triggers an impairment of osteoblasts function that could contribute to bone loss. However, these studies focused mainly on the extracellular effects of S. aureus. Our study aimed at understanding the intracellular effects of S. aureus on the early osteoblast differentiation process. In our in vitro model of osteoblast lineage infection, we first observed that internalized S. aureus 8325-4 (a reference lab strain) significantly impacted RUNX2 and COL1A1 expression compared to its non-internalized counterpart 8325-4∆fnbAB (with deletion of fnbA and fnbB). Then, in a murine model of osteomyelitis, we reported no significant effect for S. aureus 8325-4 and 8325-4∆fnbAB on bone parameters at 7 days post-infection whereas S. aureus 8325-4 significantly decreased trabecular bone thickness at 14 days post-infection compared to 8325-4∆fnbAB. When challenged with two clinical isogenic strains isolated from initial and relapse phase of the same BJI, significant impairments of bone parameters were observed for both initial and relapse strain, without differences between the two strains. Finally, in our in vitro osteoblast infection model, both clinical strains impacted alkaline phosphatase activity whereas the expression of bone differentiation genes was significantly decreased only after infection with the relapse strain. Globally, we highlighted that S. aureus internalization into osteoblasts is responsible for an impairment of the early differentiation in vitro and that S. aureus impaired bone parameters in vivo in a strain-dependent manner.

scholarly journals Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

2005 ◽  
Vol 49 (8) ◽  
pp. 3302-3310 ◽  
Author(s):  
Véronique Dartois ◽  
Jorge Sanchez-Quesada ◽  
Edelmira Cabezas ◽  
Ellen Chi ◽  
Chad Dubbelde ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Prolonged Exposure ◽  
Cyclic Peptide ◽  
Present Report ◽  
Bacterial Load ◽  
Pharmacokinetic Profile ◽  
Therapeutic Window ◽  
Infection Model

ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

scholarly journals Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

2010 ◽  
Vol 54 (12) ◽  
pp. 5115-5119 ◽  
Author(s):  
Jared L. Crandon ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Load ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Vancomycin Mics ◽  
Mrsa Strains

ABSTRACT Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log10 CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

scholarly journals Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

2016 ◽  
Vol 60 (5) ◽  
pp. 3178-3182 ◽  
Author(s):  
Megan K. Luther ◽  
Louis B. Rice ◽  
Kerry L. LaPlante
Keyword(s):  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Pharmacodynamic Model ◽  
Infection Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Time Profiles ◽  
Concentration Time ◽  
Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

scholarly journals Enterococcus faecalis persists and replicates within epithelial cells in vitro and in vivo during wound infection

2021 ◽  
Author(s):  
Wei Hong Tay ◽  
Ronni A.G. da Silva ◽  
Foo Kiong Ho ◽  
Kelvin K.L. Chong ◽  
Alexander Ludwig ◽  
...  
Keyword(s):  
Wound Infection ◽  
Enterococcus Faecalis ◽  
Opportunistic Pathogen ◽  
Small Gtpase ◽  
Infection Model ◽  
Robust Immune Response ◽  
Lysosomal Protease ◽  
The Face

Enterococcus faecalis is a frequent opportunistic pathogen of wounds, whose infections are associated with biofilm formation, persistence, and recalcitrance toward treatment. We have previously shown that E. faecalis wound infection persists for at least 7 days. Here we report that viable E. faecalis are present within both immune and non-immune cells at the wound site up to 5 days after infection, raising the prospect that intracellular persistence contributes to chronic E. faecalis infection. Using an in vitro keratinocyte infection model, we show that a subpopulation of E. faecalis becomes internalized via macropinocytosis into single membrane-bound compartments, where they can survive and replicate. These intracellular E. faecalis can persist in late endosomes up to 72 hours after infection in the absence of colocalization with the lysosomal protease cathepsin D or apparent fusion with the lysosome, suggesting that E. faecalis blocks endosomal maturation. Indeed, intracellular E. faecalis infection results in a marked reduction in Rab7 expression, a small GTPase required for endosome-lysosome fusion. Finally, we demonstrate that intracellular E. faecalis derived from infected keratinocytes are significantly more efficient in reinfecting new keratinocytes. Together, these data suggest that intracellular proliferation of E. faecalis may contribute to its persistence in the face of a robust immune response, providing a primed reservoir of bacteria for subsequent reinfection.

scholarly journals Efficacy of vancomycin and teicoplanin alone and in combination with streptomycin in experimental, low-level vancomycin-resistant, VanB-type Enterococcus faecalis endocarditis.

1996 ◽  
Vol 40 (1) ◽  
pp. 55-60 ◽  
Author(s):  
D P Nicolau ◽  
M N Marangos ◽  
C H Nightingale ◽  
K B Patel ◽  
B W Cooper ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Resistant Strain ◽  
Low Level ◽  
Vancomycin Resistant ◽  
Low Levels ◽  
High Level ◽  
Isogenic Strains ◽  
Level Resistance

The efficacy of vancomycin (VM) and teicoplanin (TE), alone and in combination with streptomycin (SM), against enterococci that express low-level VanB-type VM resistance was investigated in experimental endocarditis using isogenic strains of Enterococcus faecalis susceptible to glycopeptides and aminoglycosides or inducibly resistant to low levels of VM (MIC = 16 micrograms/ml). VM was significantly less active against the resistant strain than against the susceptible strain, establishing that low-level VanB-type VM resistance can influence therapeutic efficacy. By contrast, TE had equally good activity against both strains. VM or TE combined with SM was synergistic and bactericidal against the resistant strain in vitro. While both combinations were efficient in reducing bacterial density in vivo, TE plus SM was significantly superior to VM plus SM if valve sterilization was considered. These data suggest that despite the presence of low-level VanB-type resistance, combination therapy with a glycopeptide and SM (and presumably other aminoglycosides to which there is not high-level resistance) will nevertheless provide effective bactericidal activity.

scholarly journals The ThiL enzyme is a valid antibacterial target essential for both thiamine biosynthesis and salvage pathways in Pseudomonas aeruginosa

2020 ◽  
Vol 295 (29) ◽  
pp. 10081-10091
Author(s):  
Hyung Jun Kim ◽  
Hyunjung Lee ◽  
Yunmi Lee ◽  
Inhee Choi ◽  
Yoonae Ko ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Target ◽  
Biochemical Properties ◽  
Thiamine Pyrophosphate ◽  
Infection Model ◽  
Screening Assay ◽  
Antibiotic Development ◽  
Thiamine Biosynthesis

Thiamine pyrophosphate (TPP) is an essential cofactor for various pivotal cellular processes in all living organisms, including bacteria. Thiamine biosynthesis occurs in bacteria but not in humans; therefore, the enzymes in this pathway are attractive targets for antibiotic development. Among these enzymes, thiamine monophosphate kinase (ThiL) catalyzes the final step of this pathway, phosphorylating thiamine monophosphate to produce TPP. Here, we extensively investigated ThiL in Pseudomonas aeruginosa, a major pathogen responsible for hospital-acquired infections. We demonstrate that thiL deletion abolishes not only thiamine biosynthesis but also thiamine salvage capability and results in growth defects of the ΔthiL strain even in the presence of thiamine derivatives, except for TPP. Most importantly, the pathogenesis of the ΔthiL strain was markedly attenuated, compared with that of WT cells, with lower inflammatory cytokine induction and 103–104-fold decreased bacterial loads in an in vivo infection model in which the intracellular TPP level was in the submicromolar range. To validate P. aeruginosa ThiL (PaThiL) as a drug target, we further characterized its biochemical properties, determining a Vmax of 4.0 ± 0.2 nmol·min−1 and Km values of 111 ± 8 and 8.0 ± 3.5 μm for ATP and thiamine monophosphate, respectively. An in vitro small-molecule screening assay identified PaThiL inhibitors including WAY213613, a noncompetitive inhibitor with a Ki value of 13.4 ± 2.3 μm and potential antibacterial activity against P. aeruginosa. These comprehensive biological and biochemical results indicate that PaThiL represents a potential drug target for the development of an augmented repertoire of antibiotics against P. aeruginosa.

Repurposing Glyburide as Antileishmanial Agent to Fight Against Leishmaniasis

2019 ◽  
Vol 26 (5) ◽  
pp. 371-376 ◽  
Author(s):  
Abdur Rub ◽  
Kamal Shaker ◽  
Mohammad Kashif ◽  
Mohd Arish ◽  
Abdul Aziz Bin Dukhyil ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Culture Media ◽  
Drug Repurposing ◽  
Parasite Growth ◽  
High Rate ◽  
Mammalian Host ◽  
Dependent Manner ◽  
The World

Background: Leishmaniasis is caused by a protozoan parasite, Leishmania. It is common in more than 98 countries throughout the world. Due to insufficient availability of antileishmanial chemotherapeutics, it is an urgent need to search for new molecules which have better efficacy, low toxicity and are available at low cost. Objectives: There is a high rate of diabetic cases throughout the world that is why we planned to test the antileishmanial activity of glyburide, an effective sugar lowering drug used for the treatment of diabetes. In this study, glyburide showed a significant decrease in the parasite growth and survival in vitro in a dose-dependent manner. Methods: Anti-leishmanial activity of glyburide was checked by culturing Leishmania donovani promastigotes in the presence of glyburide in a dose and time dependent manner. Docking study against Leishmania donovani-Trypanothione synthetase (LdTrySyn) protein was performed using Autodock Vina tool. Results: Growth reversibility assay shows that growth of treated parasite was not reversed when transferred to fresh culture media after 7 days. Moreover, docking studies show efficient interactions of glyburide with key residues in the catalytic site of Leishmania donovani- Trypanothione synthetase (LdTrySyn), a very important leishmanial enzyme involved in parasite’s survival by detoxification of Nitric Oxide (NO) species, generated by the mammalian host as a defense molecule. Thus this study proves that the drug-repurposing is a beneficial strategy for identification of new and potent antileishmanial molecules. Conclusion: The results suggest that glyburide binds to LdTrySyn and inhibits its activity which further leads to the altered parasite morphology and inhibition of parasite growth. Glyburide may also be used in combination with other anti-leishmanial drugs to potentiate the response of the chemotherapy. Overall this study provides information about combination therapy as well as a single drug treatment for the infected patients suffering from diabetes. This study also provides raw information for further in vivo disease model studies to confirm the hypothesis.

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