Comparative antimicrobial activities of gatifloxacin, sitafloxacin and levofloxacin against Mycobacterium tuberculosis replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines

ABSTRACT WQ-3034 is a newly synthesized acidic fluoroquinolone. We assessed its in vitro activity against Mycobacterium tuberculosisand M. avium complex using levofloxacin (LVFX), ciprofloxacin (CPFX), sparfloxacin (SPFX), and KRM-1648 (KRM) as reference drugs. The MICs of these agents were determined by the agar dilution method with 7H11 medium. The MICs at which 50 and 90% of the test strains were inhibited (MIC50s, and MIC90s, respectively) for the test quinolones for rifampin (RMP)-susceptible M. tuberculosis strains were in the order SPFX < LVFX ≦ WQ-3034 ≦ CPFX, while those for RMP-resistant M. tuberculosis strains were in the order SPFX ≦ WQ-3034 ≦ LVFX < CPFX. The MICs of KRM for RMP-susceptible M. tuberculosis were much lower than those of the test quinolones, while the MIC90 of KRM for RMP-resistant M. tuberculosis strains was higher than those of the quinolones. The MIC50s and MIC90s of the test drugs for M. avium were in the order KRM < SPFX < CPFX ≦ WQ-3034 ≦ LVFX, while those forM. intracellulare were in the order KRM < SPFX < WQ-3034 ≒ LVFX ≦ CPFX. Next, we compared the antimicrobial activities of the test drugs against M. tuberculosisorganisms residing in cells of the Mono Mac 6 macrophage (Mφ)-like cell line (MM6-Mφs) and of the A-549 type II alveolar cell line (A-549 cells). When drugs were added at the concentration that achieves the maximum concentration in blood, progressive killing or inhibition of the M. tuberculosis organisms residing in MM6-Mφs and A-549 cells was observed in the order KRM > SPFX ≧ LVFX > WQ-3034 > CPFX. The efficacies of all quinolones against intracellular M. tuberculosis organisms were significantly lower in A-549 cells than in MM6-Mφs. WQ-3034 at the MIC caused more marked growth inhibition of intramacrophage M. tuberculosis than did LVFX. These findings indicate that the in vitro anti-M. tuberculosis activity of WQ-3034 is greater than that of CPFX and is comparable to that of LVFX.

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The immunosuppressive effects of a novel recombinant LipQ (Rv2485c) protein of Mycobacterium tuberculosis on human macrophage cell lines

Microbial Pathogenesis ◽

10.1016/j.micpath.2017.04.015 ◽

2017 ◽

Vol 107 ◽

pp. 361-367 ◽

Cited By ~ 3

Author(s):

Anjani Kumar ◽

Manisha ◽

Gurkamaljit Kaur Sangha ◽

Anju Shrivastava ◽

Jagdeep Kaur

Keyword(s):

Mycobacterium Tuberculosis ◽

Cell Lines ◽

Human Macrophage ◽

Macrophage Cell

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Immortalized dendritic like cell lines derived from mice lacking both type I and type II interferon receptors, process and present MHC II restricted antigen to primed and naive T cells, induce MLR and support virus replication

Immunology Letters ◽

10.1016/s0165-2478(97)87906-0 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 267

Author(s):

R Nunez

Keyword(s):

T Cells ◽

Cell Lines ◽

Virus Replication ◽

Type I ◽

Type Ii ◽

Naive T Cells ◽

Naïve T Cells ◽

Mhc Ii

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Design, Synthesis and Antitubercular Evaluation of New Benzimidazole Scaffolds

Anti-Infective Agents ◽

10.2174/2211352518666200108091454 ◽

2021 ◽

Vol 18 (4) ◽

pp. 375-383

Author(s):

Smriti Yadav ◽

Bharath Kumar Inturi ◽

Shrinidhi B.R ◽

Pooja H.J ◽

Neenu Ganesh ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Cell Lines ◽

Normal Cell ◽

Acyl Carrier Protein ◽

Antitubercular Activity ◽

Resistance Mechanisms ◽

Docking Studies ◽

Chemical Library ◽

Activity Data ◽

Mycobacterium Tuberculosis H37rv

Background: To overcome one of the resistance mechanisms of Isoniazid (INH), there is a need for an antitubercular agent that can inhibit InhA enzyme by circumventing the formation of INH-NAD+ adduct. Objective: The objective of the study is the development of novel antitubercular agents that target Mycobacterium tuberculosis InhA (Enoyl Acyl Carrier Protein Reductase). Methods: A small-molecule chemical library was used for the identification of the novel InhA inhibitors using primary screening and molecular docking studies followed by the scaffold hopping approach. The designed molecules, 2-(2-(hydroxymethyl)-1H- benzo[d] imidazole-1-yl)- N- substituted acetamides were synthesized by reacting (1H- benzo[d]imidazole -2-yl)methanol with appropriate 2-chloro-N-substituted acetamides / dialkylamino carbonyl chlorides respectively in good yields (42-65%). The antitubercular activity of synthesized compounds was determined by Microplate Alamar Blue Assay (MABA) against Mycobacterium tuberculosis H37Rv strain. The selected compounds were screened for cytotoxicity on normal cell lines. Results: The antitubercular activity data revealed that the 4-chlorophenyl substituted derivative (3b) showed good MIC value at 6.25 μg/mL and, dimethylacetamide substituted derivative (3i) showed MIC at 25 μg/mL among the tested compounds. The substitution of dimethylacetamide (3i) group on the 1st position of benzimidazole has good antitubercular activity (25μg/mL) in comparison to the diethyl acetamide group (3j, 100μg/mL). Conclusion: The antitubercular activity data indicated that the tested compounds exhibited well to moderate inhibition of the H37Rv strains. The compounds (3b) with electronegative substitution on the phenyl moiety exhibited better antitubercular activity than that of the other substitutions. The active compounds have displayed a good safety profile on normal cell lines.

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Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities

Molecules ◽

10.3390/molecules26113268 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3268

Author(s):

Katja S. Håheim ◽

Emil Lindbäck ◽

Kah Ni Tan ◽

Marte Albrigtsen ◽

Ida T. Urdal Helgeland ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Antimicrobial Activities ◽

Ring System ◽

Human Prostate ◽

The Novel ◽

Human Prostate Cancer ◽

Biofilm Inhibition

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

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In vitro Investigation of the Antimicrobial Activities of Novel Tetramethylpiperidine- Substituted Phenazines against Mycobacterium tuberculosis

Chemotherapy ◽

10.1159/000007255 ◽

1999 ◽

Vol 46 (1) ◽

pp. 43-48 ◽

Cited By ~ 30

Author(s):

Constance E.J. van Rensburg ◽

Gisela K. Jooné ◽

Frederick A. Sirgel ◽

Nthane M. Matlola ◽

John F. O’Sullivan

Keyword(s):

Mycobacterium Tuberculosis ◽

Antimicrobial Activities ◽

In Vitro Investigation

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Structure of the two promoters of the human lck gene: differential accumulation of two classes of lck transcripts in T cells

Molecular and Cellular Biology ◽

10.1128/mcb.9.5.2173-2180.1989 ◽

1989 ◽

Vol 9 (5) ◽

pp. 2173-2180

Author(s):

T Takadera ◽

S Leung ◽

A Gernone ◽

Y Koga ◽

Y Takihara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Carcinoma Cell ◽

Human Peripheral Blood ◽

Specific Gene ◽

Type I ◽

Type Ii ◽

Carcinoma Cell Lines ◽

Human T Cell

The human T-cell- or lymphocyte-specific gene, lck, encodes a tyrosine kinase and is a member of the src family. In this report we demonstrate that there are two classes of human lck transcripts (types I and II), containing different 5'-untranslated regions, which are expressed from two distinct promoters. No apparent sequence similarity was observed between the 5'-flanking regions of the two promoters. The expression of lck in human T-cell leukemia and carcinoma cell lines and in human peripheral blood T lymphocytes was examined by S1 nuclease and primer extension mapping and by Northern (RNA) blot analysis of total cellular RNA. The following results were obtained. (i) Two RNA start sites in the downstream promoter were used to generate type I transcripts. (ii) The major human type I start site has not been described for the mouse. (iii) At least five RNA start sites in the upstream promoter were used to generate type II transcripts. (iv) In T cells and in two colon carcinoma cell lines, type II transcripts were present in higher amounts than type I transcripts. (v) In T cells treated with phytohemagglutinin, tetradecanoylphorbol acetate, and cyclosporin A, the modulation of lck expression was associated primarily with changes in levels of type II transcripts. The above results suggest that the two human lck promoters are utilized differentially and may be regulated independently during certain physiological states.

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Quinoxaline 1,4-di-N-Oxide Derivatives: Are They Unselective or Selective Inhibitors?

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210126142541 ◽

2021 ◽

Vol 21 ◽

Author(s):

Gildardo Rivera

Keyword(s):

Mycobacterium Tuberculosis ◽

Cell Lines ◽

Mechanism Of Action ◽

Inhibitory Action ◽

Triosephosphate Isomerase ◽

Trypanothione Reductase ◽

Selective Inhibitors ◽

Oxide Ring ◽

Privileged Structure

Background: For decades, the quinoxaline 1,4-di-N-oxide ring has been considered a privileged structure to develop new antibacterial, antitumoural, and antiprotozoal agents, among others, however its mechanism of action is not clear. Objective : The main aim of this mini-review was to analyze the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives reported as antibacterial, antitumoural and antiprotozoal agents. Results : Initially, the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives against bacteria, tumoural cell lines, and parasites has been described as nonspecific, but recently, the results against different organisms have shown that these compounds have an inhibitory action on specific targets such as trypanothione reductase, triosephosphate isomerase, and other essential enzymes. Conclusion: In summary, quinoxaline 1,4-di-N-oxide is a scaffold to develop new anti-Mycobacterium tuberculosis, antitumoural and antiprotozoal agents, however, understanding the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives in each microorganism could contribute to the development of new, and more potent selective drugs.

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Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation

Biochemical Journal ◽

10.1042/bcj20180483 ◽

2018 ◽

Vol 475 (22) ◽

pp. 3687-3706 ◽

Cited By ~ 3

Author(s):

Weibing Dong ◽

Xin Zhu ◽

Xuan Zhou ◽

Ying Yang ◽

Xin Yan ◽

...

Keyword(s):

Cell Membrane ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Antimicrobial Activities ◽

Host Cells ◽

Inflammatory Factors ◽

Human Macrophage ◽

U937 Cells ◽

Wide Range ◽

Anti Inflammatory

Antimicrobial peptides have broad-spectrum killing activities against bacteria, enveloped viruses, fungi and several parasites via cell membrane permeation and exhibit primarily immunomodulatory and anti-infective functions in their interactions with host cells. However, the mechanism underlying their anti-inflammatory activity remains to be elucidated. L-K6, an analog of temporin-1CEb isolated from the skin secretion of Rana chensinensis, has demonstrated a wide range of antimicrobial activities against gram-negative and gram-positive bacteria. In this study, the potent anti-inflammatory mechanism of L-K6 and its analogs in lipopolysaccharide (LPS)-stimulated human macrophage U937 cells were evaluated. We found that L-K6 suppressed the expression of inflammatory factors by two downstream signaling components in the MyD88-dependent pathway, including the mitogen-activated protein kinases (MAPKs) and the NF (nuclear factor)-κB signaling pathway, but its analog L-K5, which had the same amino acid sequence as L-K6 but no Lys residue at the –COOH terminal, only inhibited the phosphorylation of I-κB and NF-κB. Importantly, L-K6 and L-K5 were actively taken up by U937 cells through an independent cell membrane disruption mechanism and were eventually localized to the perinuclear region. The L-K6 uptake process was mediated by endocytosis, but L-K5 was specifically taken up by U937 cells via TLR4 endocytosis. Our results demonstrated that L-K6 can neutralize LPS and diassociate LPS micelles to inhibit LPS from triggering the proinflammatory signaling pathway, and by partially inhibiting inflammatory responses by the intracellular target. However, L-K5 may mainly inhibit proinflammatory responses by intracellular reporters to modulate the NF-κB signaling pathway.

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