scholarly journals Omadacycline Potentiates Clarithromycin Activity Against Mycobacterium abscessus

2021 ◽  
Vol 12 ◽  
Author(s):  
Bui Thi Bich Hanh ◽  
Nguyen Thanh Quang ◽  
Yujin Park ◽  
Bo Eun Heo ◽  
Seunghyeon Jeon ◽  
...  
Keyword(s):  
Concentration Index ◽  
Inhibitory Concentration ◽  
Mycobacterium Abscessus ◽  
Respiratory Pathogen ◽  
Drug Resistant ◽  
Zebrafish Model ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Positive Effect

Mycobacterium abscessus is a difficult respiratory pathogen to treat, when compared to other nontuberculus mycobacteria (NTM), due to its drug resistance. In this study, we aimed to find a new clarithromycin partner that potentiated strong, positive, synergy against M. abscessus among current anti-M. abscessus drugs, including omadacycline, amikacin, rifabutin, bedaquiline, and cefoxitine. First, we determined the minimum inhibitory concentrations required of all the drugs tested for M. abscessus subsp. abscessus CIP104536T treatment using a resazurin microplate assay. Next, the best synergistic partner for clarithromycin against M. abscessus was determined using an in vitro checkerboard combination assay. Among the drug combinations evaluated, omadacycline showed the best synergistic effect with clarithromycin, with a fractional inhibitory concentration index of 0.4. This positive effect was also observed against M. abscessus clinical isolates and anti-M. abscessus drug resistant strains. Lastly, this combination was further validated using a M. abscessus infected zebrafish model. In this model, the clarithromycin-omadacyline regimen was found to inhibit the dissemination of M. abscessus, and it significantly extended the lifespan of the M. abscessus infected zebrafish. In summation, the synergy between two anti-M. abscessus compounds, clarithromycin and omadacycline, provides an attractive foundation for a new M. abscessus treatment regimen.

scholarly journals The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes

2021 ◽  
Vol 12 (1) ◽  
pp. 16-26
Author(s):  
Kimberly To ◽  
Ruoqiong Cao ◽  
Aram Yegiazaryan ◽  
James Owens ◽  
Kayvan Sasaninia ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Immune Cells ◽  
Mycobacterial Infection ◽  
Drug Resistant ◽  
Tnf Α ◽  
Resistant Strains ◽  
Ifn Γ ◽  
Drug Resistant Strains

Abstract Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects’ blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.

scholarly journals In Vitro and In Vivo Antimalarial Activities of a Carbohydrate Antibiotic, Prumycin, against Drug-resistant Strains of Plasmodia

2004 ◽  
Vol 57 (6) ◽  
pp. 400-402 ◽  
Author(s):  
KAZUHIKO OTOGURO ◽  
AKI ISHIYAMA ◽  
MIYUKI KOBAYASHI ◽  
HITOMI SEKIGUCHI ◽  
TAKASHI IZUHARA ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

scholarly journals In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.

In vitro efficacy of a synthetic all-d antimicrobial peptide against clinically isolated drug-resistant strains

2010 ◽  
Vol 35 (2) ◽  
pp. 208-209 ◽  
Author(s):  
Yoonkyung Park ◽  
Seong-Cheol Park ◽  
Jin-Young Kim ◽  
Jeong Ok Park ◽  
Chang Ho Seo ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

scholarly journals Use of the NP-40 Detergent-Mediated Assay in Discovery of Inhibitors of β-Hematin Crystallization

2011 ◽  
Vol 55 (7) ◽  
pp. 3363-3369 ◽  
Author(s):  
Rebecca D. Sandlin ◽  
Melissa D. Carter ◽  
Patricia J. Lee ◽  
Jennifer M. Auschwitz ◽  
Susan E. Leed ◽  
...  
Keyword(s):  
Drug Target ◽  
Inhibitory Concentration ◽  
Protozoan Parasite ◽  
Drug Resistant ◽  
Digestive Vacuole ◽  
Content Type ◽  
Parasite Survival ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Important Drug

ABSTRACTThe protozoan parasite responsible for malaria affects over 500 million people each year. Current antimalarials have experienced decreased efficacy due to the development of drug-resistant strains ofPlasmodiumspp., resulting in a critical need for the discovery of new antimalarials. Hemozoin, a crystalline by-product of heme detoxification that is necessary for parasite survival, serves as an important drug target. The quinoline antimalarials, including amodiaquine and chloroquine, act by inhibiting the formation of hemozoin. The formation of this crystal does not occur spontaneously, and recent evidence suggests crystallization occurs in the presence of neutral lipid particles located in the acidic digestive vacuole of the parasite. To mimic these conditions, the lipophilic detergent NP-40 has previously been shown to successfully mediate the formation of β-hematin, synthetic hemozoin. Here, an NP-40 detergent-based assay was successfully adapted for use as a high-throughput screen to identify inhibitors of β-hematin formation. The resulting assay exhibited a favorableZ′ of 0.82 and maximal drift of less than 4%. The assay was used in a pilot screen of 38,400 diverse compounds at a screening concentration of 19.3 μM, resulting in the identification of 161 previously unreported β-hematin inhibitors. Of these, 48 also exhibited ≥90% inhibition of parasitemia in aPlasmodium falciparumwhole-cell assay at a screening concentration of 23 μM. Eight of these compounds were identified to have nanomolar 50% inhibitory concentration values near that of chloroquine in this assay.

scholarly journals Semi-Synthesis of Marine-Derived Ilamycin F Derivatives and Their Antitubercular Activities

2021 ◽  
Vol 9 ◽  
Author(s):  
Jun Li ◽  
Zhiyong Liu ◽  
Mingye Hong ◽  
Changli Sun ◽  
Tianyu Zhang ◽  
...  
Keyword(s):  
Prevention And Control ◽  
Inhibitory Concentration ◽  
Drug Resistant ◽  
Structure Activity ◽  
The World ◽  
Resistant Strains ◽  
New Challenges ◽  
Low Cytotoxicity ◽  
Drug Resistant Strains ◽  
And Control

Tuberculosis (TB) is still a global disease threatening people’s lives. With the emergence of multi-drug-resistant Mycobacterium tuberculosis the prevention and control of tuberculosis faces new challenges, and the burden of tuberculosis treatment is increasing among the world. Ilamycins are novel cyclopeptides with potent anti-TB activities, which have a unique target protein against M. tuberculosis and drug-resistant strains. Herein, ilamycin F, a major secondary metabolite isolated from the marine-derived mutant strain Streptomyces atratus SCSIO ZH16 ΔilaR, is used as a scaffold to semi-synthesize eighteen new ilamycin derivatives (ilamycin NJL1–NJL18, 1–18). Our study reveals that four of ilamycin NJLs (1, 6, 8, and 10) have slightly stronger anti-TB activities against Mtb H37Rv (minimum inhibitory concentration, 1.6–1.7 μM) compared with that of ilamycin F on day 14th, but obviously display more potent activities than ilamycin F on day 3rd, indicating anti-TB activities of these derivatives with fast-onset effect. In addition, cytotoxic assays show most ilamycin NJLs with low cytotoxicity except ilamycin NJL1 (1). These findings will promote the further exploration of structure-activity relationships for ilamycins and the development of anti-TB drugs.

scholarly journals Novel isoniazid derivative as promising antituberculosis agent

2020 ◽  
Vol 15 (10) ◽  
pp. 869-879
Author(s):  
Galyna P Volynets ◽  
Michail A Tukalo ◽  
Volodymyr G Bdzhola ◽  
Nataliia M Derkach ◽  
Mykola I Gumeniuk ◽  
...  
Keyword(s):  
Resistant Strain ◽  
Inhibitory Concentration ◽  
Binding Assay ◽  
Isonicotinic Acid ◽  
Drug Resistant ◽  
Major Focus ◽  
Unbound Fraction ◽  
Protein Binding Assay ◽  
Resistant Strains ◽  
Drug Resistant Strains

Background: A major focus of tuberculosis drug discovery is aimed at the development of novel antibiotics with activity against drug-resistant strains of Mycobacterium tuberculosis. Results: We have synthesized ten isoniazid derivatives and investigated for antibacterial activity toward M. tuberculosis H37Rv and isoniazid-resistant strain SRI 1369. It was revealed that only one compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide (1), is active toward isoniazid-resistant strain with minimum inhibitory concentration value of 0.14 μM. This compound is not cytotoxic toward human liver cells (HepG2; IC50 >100 μM), demonstrates good permeability in Caco-2 cells. Accordingly to the results of plasma protein binding assay, unbound fraction of compound 1, which potentially exhibits pharmacologic effects, is 57.9%. Conclusion: Therefore, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising compound for further preclinical studies.

scholarly journals Synergistic Efficacy of β-Lactam Combinations againstMycobacterium abscessusPulmonary Infection in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Acquired Resistance ◽  
Mycobacterium Abscessus ◽  
The Novel ◽  
Content Type ◽  
Treatment Regimens ◽  
Chronic Lung Diseases ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Inhibitor Combination

ABSTRACTMycobacterium abscessusis an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinicalM. abscessusisolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several β-lactams againstM. abscessusin vitro; however, these combinations have never been tested in an animal model ofM. abscessuspulmonary disease. We utilized a recently developed murine system of sustainedM. abscessuslung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual β-lactam combinations and one β-lactam/β-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log10reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).

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