scholarly journals Galbofloxacin: A Xenometal-Antibiotic with Potent in vitro and in vivo Efficacy Against S. aureus.

2021 ◽  
Author(s):  
Apurva Pandey ◽  
Dariusz Smilowicz ◽  
Eszter Boros
Keyword(s):  
Antibacterial Activity ◽  
Clinical Success ◽  
In Vivo Efficacy ◽  
Drug Conjugates ◽  
Antibiotic Drug

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(III)...

scholarly journals Efficacy of a novel lantibiotic, CMB001, against MRSA

2021 ◽  
Author(s):  
Jerzy Karczewski ◽  
Christine M Brown ◽  
Yukari Maezato ◽  
Stephen P Krasucki ◽  
Stephen J Streatfield
Keyword(s):  
Antibacterial Activity ◽  
Pharmacokinetic Analysis ◽  
Maximum Tolerable Dose ◽  
In Vivo Efficacy ◽  
Clostridioides Difficile ◽  
Alternative Treatment Option ◽  
Significant Damage ◽  
Tolerable Dose

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.

scholarly journals 709. In Vitro Antibacterial Activity and In Vivo Efficacy of Sulbactam–Durlobactam (ETX2514SUL) Against Pathogenic Burkholderia Species

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S319-S319
Author(s):  
John O’Donnell ◽  
Alita Miller ◽  
Douglas Lane ◽  
Rekha Panchal ◽  
John P Mueller
Keyword(s):  
Antibacterial Activity ◽  
Preclinical Model ◽  
In Vivo Efficacy ◽  
Class A ◽  
Clinical Resistance ◽  
In Vitro Antibacterial Activity ◽  
Acinetobacter Spp ◽  
Lactamase Inhibitor

Abstract Background The genus Burkholderia contains several pathogenic species with distinct etiologies, including Burkholderia pseudomallei the biothreat pathogen responsible for melioidosis and Burkholderia mallei which causes glanders. β-Lactams, such as ceftazidime and meropenem, are important therapeutic options for these infections. However, clinical resistance to β-lactams, which is primarily mediated by multiple types of β-lactamases in these species, is a growing concern. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Sulbactam (SUL) is an Ambler Class A β-lactamase inhibitor with intrinsic antibacterial activity against a limited number of species, including Acinetobacter spp. SUL-DUR is currently in Phase 3 clinical testing for the treatment of carbapenem-resistant infections caused by Acinetobacter spp. In this study, SUL-DUR was tested for in vitro antibacterial activity against B. pseudomallei and B. mallei as well as for in vivo efficacy in a preclinical model of melioidosis. Methods The antibacterial activity of SUL alone or in combination with DUR (fixed at 4 mg/L) against B. pseudomallei (n = 30) and B. mallei (N = 28) was determined following CLSI guidelines. In vivo efficacy was tested in an acute murine model of melioidosis in which 4 × 104 cfu Bp K96423 (SUL-DUR MIC = 1 mg/L) was administered intranasally to BalbC mice. SUL-DUR (100/200 or 400/200 mg/kg) was administered q4h subcutaneously 4 hours post-challenge for 6 days and murine survival was monitored for 45 days. Doxycycline (DOX) and ciprofloxacin (CIP) were dosed as positive controls at 40 mg/kg q12 h for 6 days. Results The addition of DUR effectively lowered the SUL MIC50/90 from 8/16 to 0.25/0.5 mg/L vs. B. pseudomallei and from 8/8 to 1/2 mg/L for B. mallei. All untreated mice in the melioidosis model succumbed to infection within 3 days of challenge. 60% survival was observed for both dose arms of SUL-DUR as compared with 40% survival observed for both CIP and DOX. Conclusion Preliminary preclinical data demonstrating robust in vitro and in vivo antibacterial activity of SUL-DUR against Burkholderia spp. suggests this combination may be an effective new therapy for the treatment of these challenging pathogens. Disclosures All authors: No reported disclosures.

scholarly journals Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Santucci ◽  
Daniel J. Greenwood ◽  
Antony Fearns ◽  
Kai Chen ◽  
Haibo Jiang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Combination Chemotherapy ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Human Macrophages ◽  
Ion Microscopy ◽  
Intracellular Localisation

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

scholarly journals The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health

2021 ◽  
Vol 22 (6) ◽  
pp. 3253
Author(s):  
Clarisse Roblin ◽  
Steve Chiumento ◽  
Cédric Jacqueline ◽  
Eric Pinloche ◽  
Cendrine Nicoletti ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Human Health ◽  
Biological Activities ◽  
Resistant Bacteria ◽  
Modified Peptides ◽  
The 1960S ◽  
Conventional Antibiotics ◽  
Clinical Potential

The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest.

scholarly journals P074 In vitro and in vivo efficacy of linezolid on Treponema pallidum, the syphilis agent

2021 ◽  
Author(s):  
L Giacani ◽  
A Haynes ◽  
M Vall Mayans ◽  
M Ubals Cazorla ◽  
C Nieto ◽  
...  
Keyword(s):  
Treponema Pallidum ◽  
In Vivo Efficacy

scholarly journals Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 927
Author(s):  
Sebas D. Pronk ◽  
Erik Schooten ◽  
Jurgen Heinen ◽  
Esra Helfrich ◽  
Sabrina Oliveira ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Single Domain ◽  
Drug Conjugates ◽  
Intracellular Drug Delivery ◽  
Internalization Rate ◽  
Single Domain Antibodies ◽  
Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

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