scholarly journals Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 381
Author(s):  
Lara Muñoz-Muñoz ◽  
Carolyn Shoen ◽  
Gaye Sweet ◽  
Asunción Vitoria ◽  
Tim J. Bull ◽  
...  
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Mycobacterium Ulcerans ◽  
Health Concern ◽  
Macrocyclic Lactones ◽  
Wide Range ◽  
Poor Treatment ◽  
Spectrum Activity ◽  
Time Kill ◽  
Broad Spectrum Activity

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

scholarly journals In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 355
Author(s):  
Unai Caballero ◽  
Sarah Kim ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Valvanera Vozmediano ◽  
...  
Keyword(s):  
Interaction Model ◽  
Antifungal Drugs ◽  
Health Concern ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Wide Range ◽  
Time Kill

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.

scholarly journals Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
David Wensel ◽  
Yongnian Sun ◽  
Zhufang Li ◽  
Sharon Zhang ◽  
Caryn Picarillo ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
High Affinity ◽  
Glycosylation Sites ◽  
Spectrum Activity ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Broad Spectrum Activity

ABSTRACT A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.

scholarly journals In vitro Insecticidal and Time-Kill Profile of Ethyl Acetate Extract of Marine Streptomyces sp. Isolated from Sundarbans, Bangladesh

2015 ◽  
Vol 17 (2) ◽  
pp. 151-156 ◽  
Author(s):  
Md Anwarul Haque ◽  
Ashish Kumar Sarker ◽  
Mohammad Sayful Islam ◽  
Md Ajijur Rahman ◽  
Md Akter Uzzaman Chouduri ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Mangrove Forest ◽  
Bacterial Strains ◽  
Streptomyces Species ◽  
Streptomyces Sp ◽  
Cell Counts ◽  
Wide Range ◽  
Marine Streptomyces ◽  
Time Kill

The marine soil and sediment samples were collected from different locations of mangrove forest Sundarbans, Bangladesh the largest tidal halophytic mangrove forest in the world. A total of twenty nine Actinomycete strains (AIAH-1 to AIAH-29) were isolated by serial dilution method using isolation media. Among twenty nine strains, AIAH-10 was selected for further study due to its potent antibacterial activity against a wide range of pathogenic bacterial strains. On the basis of morphological, cultural and biochemical studies, the strain AIAH-10 was assigned to Streptomyces sp. The present study was designed to investigate the in vitro insecticidal and time-kill profile of ethyl acetate extracts of marine Streptomyces sp. A dose dependent mortality was observed against the larvae of Sitophilus oryzae. The larval mortality was recorded as 100% in the concentration of 80 mg/ml and higher concentrations, LC50 was found as 11.48 mg/ml. The minimum inhibitory concentration was recorded as 8 to 32 mg/ml against six different pathogenic bacterial strains. Average Log10 reductions in viable cell counts for the extracts ranged from 1.91 Log10 and 2.86 Log10 cfu/mL after 3 h interaction and 2.10 Log10 and 2.93 Log10 after 6 h interaction at MIC, 2 × MIC, 3 × MIC and 4 × MIC concentrations. This investigation reveals that the Streptomyces species isolated from Sundarbans, Bangladesh may be interesting source for the isolation of potent bioactive compounds. DOI: http://dx.doi.org/10.3329/bpj.v17i2.22332 Bangladesh Pharmaceutical Journal 17(2): 151-156, 2014

scholarly journals 694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S314-S314
Author(s):  
Alita Miller ◽  
Sarah McLeod ◽  
Tarun Mathur ◽  
Ian Morrissey
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Package Insert ◽  
Multidrug Resistant ◽  
Antibiotic Resistant ◽  
Carbapenem Resistant ◽  
In Vitro Antibacterial Activity ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India. Methods A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert. Results As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR. Conclusion The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii. Disclosures All authors: No reported disclosures.

scholarly journals Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2

2020 ◽  
Vol 11 (12) ◽  
pp. 1379-1385
Author(s):  
R. Kirk ◽  
A. Ratcliffe ◽  
G. Noonan ◽  
M. Uosis-Martin ◽  
D. Lyth ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Infections ◽  
Rational Design ◽  
Topoisomerase Ii ◽  
Topoisomerase Inhibitors ◽  
Design Synthesis ◽  
Pharmacokinetic Properties ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

We disclose the discovery of REDX07965, a novel tricyclic topoisomerase inhibitor (NTTI) which has broad spectrum activity, favourable in vitro pharmacokinetic properties and selectivity versus human topoisomerase II.

scholarly journals Enhanced Resistance to Bacterial Infection in Protegrin-1 Transgenic Mice

2008 ◽  
Vol 52 (5) ◽  
pp. 1812-1819 ◽  
Author(s):  
Queenie C. K. Cheung ◽  
Patricia V. Turner ◽  
Cheng Song ◽  
De Wu ◽  
Hugh Y. Cai ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bacterial Infection ◽  
Ectopic Expression ◽  
Farm Animals ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Cell Counts ◽  
Enhanced Resistance ◽  
Wide Range

ABSTRACT Antibiotic-resistant bacteria have become a public health concern. It was suggested that one source of resistant pathogens may be food-producing animals. Alternative approaches are therefore needed to enhance the resistance of farm animals to bacterial infection. Protegrin-1 (PG-1) is a neutrophil-derived antimicrobial peptide that possesses activity against a wide range of bacteria and enveloped viruses. Here we report on the production of transgenic mice that ectopically expressed PG-1 and compare their susceptibilities to Actinobacillus suis infection with those of their wild-type (WT) littermates. Of the 126 mice that were challenged with A. suis, 87% of the transgenic mice survived, whereas 31% of their WT littermates survived. The PG-1 transgenic mice had significantly lower bacterial loads in their lungs and reduced numbers of pulmonary pathological lesions. The antimicrobial function of PG-1 was confirmed in vitro by using fibroblast cells isolated from the transgenic mice but not the WT mice. Moreover, differential blood cell counts in bronchoalveolar lavage fluid indicated greater number of neutrophils in PG-1 transgenic mice than in their WT littermates after bacterial challenge. Our data suggest that the ectopic expression of PG-1 in mice confers enhanced resistance to bacterial infection, laying the foundation for the development of livestock with improved resistance to infection.

scholarly journals Pharmacodynamics and Bactericidal Activity of Moxifloxacin in Experimental Escherichia coliMeningitis

2001 ◽  
Vol 45 (11) ◽  
pp. 3092-3097 ◽  
Author(s):  
Violeta Rodriguez-Cerrato ◽  
Cynthia C. McCoig ◽  
Ian C. Michelow ◽  
Faryal Ghaffar ◽  
Hasan S. Jafri ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Rabbit Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
E Coli ◽  
Pharmacodynamic Profile ◽  
Spectrum Activity ◽  
Csf Concentration ◽  
Broad Spectrum Activity

ABSTRACT Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia colimeningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C max) values were 1.8, 4.2, and 4.9 μg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 μg/ml · h, respectively, and the half-life values (t ½) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Δlog10 CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were −5.70, −6.62, and −7.02; −7.37, −7.37, and −6.87; and −6.62, −6.62, and −6.62, respectively, whereas those of ceftriaxone and meropenem were −4.18, −5.24, and −4.43, and −3.64, −3.59, and −4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C max/MBC were interrelated (r = 0.81); there was less correlation withT > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicatingE. coli from CSF.

scholarly journals Tebipenem as an oral alternative for the treatment of typhoid caused by extensively drug resistant (XDR) Salmonella Typhi

2021 ◽  
Author(s):  
Elli Mylona ◽  
Phat Voong Vinh ◽  
Sonia Qureshi ◽  
Abhilasha Karkey ◽  
Sabina Dongol ◽  
...  
Keyword(s):  
Enteric Fever ◽  
Salmonella Typhi ◽  
Drug Resistant ◽  
Extensively Drug Resistant ◽  
Extensive Drug Resistance ◽  
Spectrum Activity ◽  
Fever Treatment ◽  
Emergence Of Resistance ◽  
Broad Spectrum Activity

Abstract The emergence of multi-drug (MDR) and extensive-drug resistance (XDR) in Salmonella Typhi and Paratyphi A hinder efficacious out-patient enteric fever treatment. We show that non-XDR and XDR S. Typhi and S. Paratyphi A are susceptible to the carbapenem tebipenem in vitro. Tebipenem demonstrated partial synergy with antimicrobials including azithromycin, signifying combination therapy may limit the emergence of resistance. Given recent evidence on tebipenem inhibitory activity against MDR Shigella, its broad-spectrum activity against MDR/XDR organisms renders it a good clinical trial candidate.

scholarly journals Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes

2021 ◽  
Vol 17 (2) ◽  
pp. e1009110
Author(s):  
Laura I. Levi ◽  
Veronica V. Rezelj ◽  
Annabelle Henrion-Lacritick ◽  
Diana Erazo ◽  
J Boussier ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Broad Spectrum ◽  
Chikungunya Virus ◽  
Rna Virus ◽  
Viral Genomes ◽  
Mosquito Cells ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.

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