scholarly journals Clomiphene Citrate Shows Effective and Sustained Antimicrobial Activity against Mycobacterium abscessus

2021 ◽  
Vol 22 (20) ◽  
pp. 11029
Author(s):  
Da-Gyum Lee ◽  
Yoo-Hyun Hwang ◽  
Eun-Jin Park ◽  
Jung-Hyun Kim ◽  
Sung-Weon Ryoo
Keyword(s):  
Clomiphene Citrate ◽  
Treatment Success ◽  
In Vitro Study ◽  
Drug Efficacy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Wild Type ◽  
Antimicrobial Drugs ◽  
Resistant Strains

Mycobacterium abscessus (M. abscessus) causes chronic pulmonary infections and is the most difficult non-tuberculous mycobacteria (NTM) to treat due to its resistance to current antimicrobial drugs, with a treatment success rate of 45.6%. Thus, novel treatment drugs are needed, of which we identified the drug clomiphene citrate (CC), known to treat infertility in women, to exhibit inhibitory activity against M. abscessus. To assess the potential of CC as a treatment for M. abscessus pulmonary diseases, we measured its efficacy in vitro and established the intracellular activity of CC against M. abscessus in human macrophages. CC significantly inhibited the growth of not only wild-type M. abscessus strains but also clinical isolate strains and clarithromycin (CLR)-resistant strains of M. abscessus. CC’s drug efficacy did not have cytotoxicity in the infected macrophages. Furthermore, CC worked in anaerobic non-replicating conditions as well as in the presence of biofilm. The results of this in vitro study on M. abscessus activity suggest the possibility of using CC to develop new drug hypotheses for the treatment of M. abscessus infections.

scholarly journals 10-DEBC Hydrochloride as a Promising New Agent against Infection of Mycobacterium abscessus

2022 ◽  
Vol 23 (2) ◽  
pp. 591
Author(s):  
Da-Gyum Lee ◽  
Hye-Jung Kim ◽  
Youngsun Lee ◽  
Jung-Hyun Kim ◽  
Yoohyun Hwang ◽  
...  
Keyword(s):  
Treatment Success ◽  
In Vitro Study ◽  
Drug Efficacy ◽  
Mycobacterium Abscessus ◽  
Embryonic Cell ◽  
Pulmonary Infections ◽  
Akt Inhibitor ◽  
Antimicrobial Drugs ◽  
The Mean

Mycobacterium abscessus (M. abscessus) causes chronic pulmonary infections. Its resistance to current antimicrobial drugs makes it the most difficult non-tuberculous mycobacteria (NTM) to treat with a treatment success rate of 45.6%. Therefore, there is a need for new therapeutic agents against M. abscessus. We identified 10-DEBC hydrochloride (10-DEBC), a selective AKT inhibitor that exhibits inhibitory activity against M. abscessus. To evaluate the potential of 10-DEBC as a treatment for lung disease caused by M. abscessus, we measured its effectiveness in vitro. We established the intracellular activity of 10-DEBC against M. abscessus in human macrophages and human embryonic cell-derived macrophages (iMACs). 10-DEBC significantly inhibited the growth of wild-type M. abscessus and clinical isolates and clarithromycin (CLR)-resistant M. abscessus strains. 10-DEBC’s drug efficacy did not have cytotoxicity in the infected macrophages. In addition, 10-DEBC operates under anaerobic conditions without replication as well as in the presence of biofilms. The alternative caseum binding assay is a unique tool for evaluating drug efficacy against slow and nonreplicating bacilli in their native caseum media. In the surrogate caseum, the mean undiluted fraction unbound (fu) for 10-DEBC is 5.696. The results of an in vitro study on the activity of M. abscessus suggest that 10-DEBC is a potential new drug for treating M. abscessus infections.

scholarly journals Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Albertus Viljoen ◽  
Clément Raynaud ◽  
Matt D. Johansen ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Adjunctive Therapy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Strains ◽  
High Doses ◽  
Clinical Potential

ABSTRACT Due to intrinsic multidrug resistance, pulmonary infections with Mycobacterium abscessus are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against Mycobacterium abscessus both in vitro and in vivo. Here, we report that verapamil improves the efficacy of bedaquiline activity against M. abscessus clinical isolates and low-level resistant strains, both in vitro and in macrophages. Verapamil may have clinical potential as adjunctive therapy provided that sufficiently high doses can be safely achieved.

scholarly journals Pharmacodynamics of Itraconazole against Aspergillus fumigatus in anIn VitroModel of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration

2012 ◽  
Vol 56 (8) ◽  
pp. 4146-4153 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Ajay Sudan ◽  
Adam R. Jeans ◽  
Lea Gregson ◽  
Joanne Goodwin ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Content Type ◽  
Exposure Response ◽  
Prevention And Treatment ◽  
Resistant Infection ◽  
Resistant Strains ◽  
Type Strains

ABSTRACTItraconazole is used for the prevention and treatment of infections caused byAspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. Anin vitromodel of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.

scholarly journals In vitro and intracellular activity of imipenem combined with tedizolid, rifabutin, and avibactam against Mycobacterium abscessus

2018 ◽  
Author(s):  
Eva Le Run ◽  
Michel Arthur ◽  
Jean-Luc Mainardi
Keyword(s):  
Inhibitory Concentration ◽  
Antibacterial Activities ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Once Daily ◽  
Minimal Inhibitory Concentrations ◽  
Recommended Treatment ◽  
The Impact ◽  
Lactamase Inhibitor

Mycobacterium abscessus has emerged as a significant pathogen responsible for chronic pulmonary infections in cystic fibrosis (CF) patients, which are difficult to treat due to resistance to a broad range of antibiotics. The initial phase of the recommended treatment in CF patients includes imipenem used without any β-lactamase inhibitor in spite of the production of the β-lactamase BlaMab. Here, we determine whether the addition of tedizolid, a once-daily oxazolidinone, improves the activity of imipenem alone or in combination with a β-lactamase inhibitor, avibactam, and rifabutin.The activity of the drugs was evaluated against M. abscessus CIP104536 by determining in vitro and intracellular antibacterial activities. The impact of BlaMab inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and its β-lactamase-deficient derivative (ΔblaMab).The minimal inhibitory concentrations (MICs) of tedizolid against M. abscessus CIP104536 and ΔblaMab were 4 μg/mL. Tedizolid combined with imipenem showed a moderate synergistic effect with fractional inhibitory concentration (FIC) indexes of 0.41 and 0.38 for CIP104536 and ΔblaMab, respectively. For both strains, the addition of tedizolid at 2 μg/mL, corresponding to the peak serum concentration, increased the intracellular efficacy of imipenem at 8 and 32 μg/mL. Addition of avibactam and rifabutin improved the activity of the imipenem-tedizolid combination against CIP104536S.The imipenem-tedizolid combination should be further considered for the treatment of M. abscessus pulmonary infections in CF patients. The efficacy of the treatment might benefit from the use of a β-lactamase inhibitor, such as avibactam, and the addition of rifabutin.

scholarly journals Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Mutants ◽  
Lactamase Inhibitor ◽  
Selection Of

ABSTRACTMycobacterium abscessusis a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease.M. abscessusis intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan inM. abscessusis achieved via two enzyme classes,l,d- andd,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killingM. abscessus. Paired combinations of antibiotics tested forin vitrosynergy againstM. abscessusincluded dual β-lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistantM. abscessusinfections.

scholarly journals Development and Significance of Dicarboximide Resistance in Sclerotinia minor Isolates from Commercial Lettuce Fields in California

Plant Disease ◽  
1997 ◽  
Vol 81 (2) ◽  
pp. 148-153 ◽  
Author(s):  
J. C. Hubbard ◽  
K. V. Subbarao ◽  
S. T. Koike
Keyword(s):  
Fungicide Resistance ◽  
Disease Incidence ◽  
Vegetative Mycelium ◽  
Wild Type ◽  
In Vitro Production ◽  
Field Isolates ◽  
Resistant Strains ◽  
Measurable Growth ◽  
Vitro Production

Three growth stages of each of 20 Sclerotinia minor isolates were tested for resistance to iprodione. Sclerotia and both vegetative and mature mycelium of each isolate were plated on potato-dextrose agar (PDA) amended with 0, 1, 5, 10, 25, and 100 µg of the fungicide per ml, and radial growth was measured. All wild-type field isolates were initially sensitive and did not grow in the presence of iprodione. However, fungicide resistance arose readily in vitro. All 20 isolates produced measurable growth (≥2 mm) on iprodione at 5 µg/ml after 2 weeks when started from mature mycelium, and 18 of 20 isolates produced measurable growth after 4 weeks when started from vegetative mycelium. In general, fungicide-resistant growth arose more frequently and mean colony diameters were significantly greater (P ≤ 0.05) with mature mycelium than with vegetative mycelium at all times and concentrations. In sclerotial germination tests, at least 1% of sclerotia germinated in 18 of 20 isolates after 2 weeks on iprodione at 5 µg/ml, and in 19 of 20 isolates after 5 weeks on 100 µg/ml. Of growth produced on 79 plates containing iprodione, 73 remained viable on PDA after 5 months, and 71 retained resistance to 5 µg/ml. Seventy of these also exhibited cross-resistance to vinclozolin, another dicarboximide fungicide. Pathogenicity of five fungicide-resistant strains was tested in greenhouse, microplot, and field experiments, with and without iprodione. Two months after in vitro production, one of the five resistant strains was avirulent, but disease incidence for the other four ranged from 40 to 75%, compared with 40% for the wild-type isolates. However, the virulence of the fungicide-resistant strains declined over time. Ten months after their production, two of the isolates were avirulent and disease incidence for the others ranged from 3 to 17%, compared with 40 to 90% for the wild-type isolates. The strains that remained virulent 5 and 7 months after in vitro production were not significantly controlled by iprodione sprayed according to labeled rates, although disease was significantly controlled by the fungicide in treatments inoculated with wild-type field isolates (P > 0.05). In experiments in commercial fields to determine the efficacy of fungicide sprays on the wild-type S. minor population, there was no evidence that fungicide resistance was the cause of lack of lettuce drop control observed in many coastal California fields. Application of fungicides at a less than optimal time may account for some incidents of control failure.

scholarly journals Skin-Derived Precursor Cells as an In Vitro Modelling Tool for the Study of Type 1 Neurofibromatosis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Araika Gutiérrez-Rivera ◽  
Haizea Iribar ◽  
Anna Tuneu ◽  
Ander Izeta
Keyword(s):  
In Vitro Study ◽  
Neurofibromatosis Type ◽  
Precursor Cells ◽  
Cell Of Origin ◽  
Wild Type ◽  
Multipotent Progenitor Cells ◽  
Clonal Origin ◽  
Lines Of Evidence

The most characteristic feature of neurofibromatosis type 1 (NF1) is the development of neurofibromas. It has been suggested that these tumors are caused by somatic inactivation of the wild-typeNF1allele, but the cell that originally suffers this mutation remains controversial. Several lines of evidence support the clonal origin of these tumors, and it has been recently suggested that skin-derived precursor cells (SKPs) could be the cell of origin of dermal neurofibromas. Nullizygous (NF1−/−) SKPs do give rise to neurofibromas when transplanted to heterozygous mice. Moreover, a nullizygous population of cells that is S100βnegative is present in human neurofibromas, andNF1+/−multipotent progenitor cells are seemingly recruited to the tumor. This evidence supports the neurofibroma stem cell hypothesis and a putative involvement of SKPs in the aetiopathogenesis of the disease, suggesting that SKPs could become a valuable tool for the in vitro study of NF1.

scholarly journals Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia

2004 ◽  
Vol 48 (1) ◽  
pp. 80-85 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos
Keyword(s):  
Mouse Model ◽  
Lung Tissue ◽  
Resistant Strain ◽  
Peptide Deformylase ◽  
In Vitro Activity ◽  
Wild Type ◽  
Virulent Strains ◽  
Resistant Strains

ABSTRACT The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 105 CFU (virulent strains) into immunocompetent mice or 107 CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.

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