Mycobacterium Tuberculosis H37Rv Strain Research Articles

IRAK1 and IRAK4 signaling proteins are dispensable in the response of human neutrophils to Mycobacterium tuberculosis infection.

The involvement of neutrophils in the host response to Mycobacterium tuberculosis (Mtb) infection is not as well recognized as the involvement of macrophages and dendritic cells. Thus, this study gives more insight on the impact of the virulent Mtb H37Rv strain on proapoptotic and proinflammatory functions of human neutrophils in vitro. We found that neutrophils are not able to kill Mtb during the infection process, probably due to the lack of reactive oxygen species and nitric oxide production in response to bacteria. However, infected neutrophils effectively released cytokines, chemoattractant interleukin (IL) 8 and proinflammatory IL-1β. Moreover, Mtb enhanced the early apoptosis of neutrophils at 2 h postinfection. Additionally, this proapoptotic and proinflammatory response of neutrophils to Mtb infection occurred in an IRAK1- and IRAK4-independent manner. We also found that Mtb did not affect the surface expression of Toll-like receptor (TLR) 2 and slightly enhanced the surface expression of TLR4, but did not influence mRNA levels of both TLRs during the infection process. In conclusion, we show that the inhibition of signaling proteins activated by MyD88-dependent pathway did not participate in the biological activity of neutrophils against Mtb.

Click chemistry based regioselective one-pot synthesis of coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones as newer potent antitubercular agents.

Coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8k-z) were synthesized via copper(I)-catalyzed azide-alkyne cycloadditionclick chemistry. The synthesized hybrid molecules were characterized by spectral studies. Compounds 8k-z were screened for their in vitro anti-TB activity by using the Microplate Alamar Blue assay and for cytotoxicity using the MTT assay. Some of the compounds were found to be most potent against the tested Mycobacterium tuberculosis H37Rv strain with a MIC of 1.60 µg/ml. Further, docking the compounds into the InhA binding pocket showed strong binding interactions and effective overall docking scores were recorded. The drug-likeness and toxicity studies were computed using Molinspiration and Protox, respectively.

Evaluation of crystal violet decolorization assay and resazurin microplate assay for antimycobacterial screening

The main obstacle in antimycobacterial discovery is the extremely slow growth rates of pathogenic mycobacteria that lead to the long incubation times needed in antimycobacterial screening. Some in vitro testings has been developed and are currently available for antimycobacterial screening. The aim of the study was to compare Resazurin Microplate Assay (REMA) and Crystal Violet Decolorization Assay (CVDA) for testing mycobacteria susceptibility to isoniazid and rifampicin as well as for antimycobacterial screening of natural products (NP). Mycobacterium tuberculosis strain H37Rv and Mycobacterium smegmatis strain mc2 155 were used as tested mycobacteria. Serial two-fold dilutions from 0.0625 to 1.0 μg/mL for the isoniazid and rifampicin and from 6.25 to 100.0 μg/mL for the NP A and B were prepared. Tested mycobacteria were then incubated with tested drugs or NPs in each growth medium at 37 °C for 7 days for M. tuberculosis and 3 days for M. smegmatis. MIC values against M. tuberculosis were interpreted 24–48 h after adding resazurin or at least 72 h after adding crystal violet, whereas MIC values against M. smegmatis were interpreted 1 h after adding resazurin or 24 h after adding crystal violet. The MIC values against M. tuberculosis interpreted by REMA were 0.0625, 0.0625, 6.25, and >100 μg/mL for rifampicin, isoniazid, NP A, and NP B, respectively, and those interpreted by CVDA were 0.0625, 0.0625, 6.25, and >100 μg/mL for rifampicin, isoniazid, NP A, and NP B, respectively. Moreover, the MIC values against M. smegmatis interpreted by REMA were 0.0625, >1, 6.25, and 100 μg/mL for rifampicin, isoniazid, NP A, and NP B, respectively, and those interpreted by CVDA were 0.125, >1, 6.25, and >100 μg/mL for rifampicin, isoniazid, NP A, NP B respectively. In conclusion, REMA is faster and easier than CVDA to interpret MIC values, however CVDA produces higher MIC values than REMA for rifampicin and NP B in M. smegmatis susceptibility testing. Therefore, REMA and CVDA can be used for antimycobacterial screening.

Characteristic genes in THP‑1 derived macrophages infected with Mycobacterium tuberculosis H37Rv strain identified by integrating bioinformatics methods.

Mycobacterium tuberculosis (M. tb) is a highly successful pathogen that has co-existed with humans for 1,000's of years. As the cornerstone of the immune system, macrophages are a key part of innate immunity. They ingest and degrade foreign substances including aging cells and microorganisms, coordinate the inflammatory process, and are the first line of defense against M. tb infection. Recent advances in cellular mycobacteriology have indicated that M. tb uses an remarkably complex strategy to disrupt macrophage function, in order to counteract the antimicrobial mechanisms of the innate and adaptive immune responses, thereby achieving immune escape. With the popularity of microarray technology, a variety of public platforms have provided a variety of gene expression data associated with physiological and disease conditions. Meta-analysis can systematically and quantitatively analyze multiple independent data concerning the same disease, greatly improving the statistical significance and credibility of the gene expression data analysis performed. In the present study, 6 microarray expression datasets of human acute monocytic leukemia THP-1 cell line infected by M. tb H37Rv strain were collected from the GEO database. A total of 4 high-quality datasets were identified using meta-analysis methods in R language, and 306 differentially expressed genes with statistical significance were obtained. Then, a protein-protein interaction (PPI) network of these differentially expressed genes was constructed on the Search Tool for the Retrieval of Interacting Genes/Proteins Database online tool and visualized by Cytoscape v. 3.6.1 software. Using CentiScape and MCODE plugin in the Cytoscape software to mine the functional modules associated with M. tb infection process, 32 characteristic genes were identified. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis was performed on the 32 characteristic genes, and it was demonstrated that these genes were primarily associated with the type I interferon (IFN) pathway. In the established model of THP-1-derived macrophages infected by M. tb, the actual differential expression levels of IFN-stimulated gene 15 (ISG15), 2′-5-oligoadenylate synthetase like (OASL), IFN regulatory factor 7 (IRF7) and DExD/H-box helicase 58 (DDX58), the first 4 genes of the 32 characteristic genes, were verified by reverse transcription quantitative polymerase chain reaction. The results were consistent with the results of microarray analysis. The association between ISG15, OASL and IRF7 and TB infection was also verified. Although a number of studies have identified that the type I IFN pathway may assist M. tb to achieve immune escape, the present study used a meta-analysis of microarray data and PPI network analysis to examine some of the novel genes identified in the IFN pathway. The results furthered the understanding of the molecular mechanisms of the TB immune response and provided a novel perspective for future therapeutic goals.

N-(2-Phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides containing various amine moieties: Design, synthesis and antitubercular activity

Seven 2,6-disubstituted N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide series containing various amine moieties were designed and synthesized as new anti-TB agents. Many of them show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and two MDR-MTB clinical isolates (MIC: < 0.002–0.030 μg/mL). Compounds 2f, 5e and 5g display acceptable safety and pharmacokinetic profiles, opening a new direction for further development.

Synthesis, antitubercular evaluation, molecular docking and molecular dynamics studies of 4,6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles

A new series of novel diphenyl ether based 2-oxo-dihydropyridine derivatives were synthesized and screened for their in vitro antimycobacterial and antibacterial activities. Most of the synthesized compounds showed significant activity against Mycobacterium tuberculosis H37Rv strain in comparison to triclosan. Among them, compounds 3k and 3q were found to be most active against Mycobacterium tuberculosis H37Rv strain with MIC of 31 and 32 μM respectively. All the compounds were found to be more active against Bacillus subtilis and Staphylococcus aureus than against Pseudomonas aeruginosa and Escherichia coli. Several compounds were found to safe against Vero and HepG2 cell lines. Molecular docking study was utilized to explore the binding mode of the synthesized compounds to the target enzyme InhA. The results showed reasonable binding interactions of synthesized molecules and good dock score. Molecular dynamics studies were performed in order to support the docking results. The compound 3k-InhA complex was found to be more stable and exhibited more interaction when compared to Triclosan. The compounds followed Lipinski rule of five and displayed acceptable pharmacokinetic properties depicted via in silico studies.

The Biology Activities of Isonicotinohydrazide Derivatives as an Anti-tuberculosis Candidate

The compound N’-(3-chlorobenzoyl)isonicotinohydrazide, N’-(3-bromobenzoyl) isonicotinodyrazide, N’-(4-fluorobenzoyl)isonicotinohydrazide are isonicotinohydrazide derivative compounds which have antibacterial activity against bacteria Staphylococcus aureus, bacteria Bacillus subtilis as gram-positive Escherichia coli as gram-negative, and against strain Mycobacterium tuberculosis H37Rv. The purpose of this study was to obtain antituberculous candidates from isonicotinohydrazide compounds. The method used to test the antibacterial activity was the disc diffusion while for antimycobacterium using method Resazurin Microtiter Assay (REMA). The results of the antibacterial activity test on the bacteria Staphylococcus aureus compound N’-(3-chlorobenzoyl)isonicotinohydrazide had the lowest MIC value (0.26 ppm), while the bacteria Bacillus subtilis and Escherichia coli compound with the lowest MIC value of N’-(3-bromobenzoil)isonicotinodyrazide with a MIC value of 0.30 and 0,24 ppm. In the bacterium M. tuberculosis, H37Rv compound isoniazid has the smallest MIC value (3.125 ppm).

Design, synthesis, and antimycobacterial activity of novel ciprofloxacin derivatives.

Tuberculosis is the deadliest infectious disease affecting humankind with a death toll of approximately 1.7 million people in 2016. The increasing prevalence of multidrug-resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (CPX) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent Mtb H37Rv strain in vitro. The small propionyl analogue 11 (MIC90 1.6μM; SI>61) and the large cholesteryl hybrid 32 (MIC90 2.0μM; SI>6) were the most active derivatives, comparable to CPX (MIC90 1.8μM). However, the slightly less active but non-cytotoxic para-fluorobenzyl hybrid 28 (MIC90 3.7μM; SI 27) was more selective toward bacteria than 32. Thus, the CPX derivatives 11 and 28 were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models.

Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.

Impact of bedaquiline and capreomycin on the gene expression patterns of multidrug-resistant Mycobacterium tuberculosis H37Rv strain and understanding the molecular mechanism of antibiotic resistance.

The emergence of multidrug resistance (MDR), extensively drug-resistant, and total drug-resistant Mycobacterium tuberculosis (Mtb) strains have hampered the treatment of tuberculosis (TB). Capreomycin and Bedaquiline are currently used for MDR-TB treatment. To understand the impact of these antibiotics on Mtb genes, we have curated the gene expression data where the Mtb cultures were exposed to the Bedaquiline and Capreomycin. Based on the P value cut off (<0.05) and logFC (<-0.5 and >+0.5) values, we have selected the top differentially expressed genes during the antibiotic exposures. We have observed that the top differentially expressed Mtb genes were related to universal stress genes, two-component regulatory systems, and drug efflux pumps. We have curated the Mtb gene datasets and carried out the functional over-representation analysis using the individual gene expression values. We further, constructed the gene interaction networks of antibiotic resistance genes and virulence genes of Mtb to understand the impact of the antibiotics at the molecular level and thus to understand the antimicrobial resistance and virulence patterns. Our study elucidates the impact of antibiotics on the Mtb genes at the molecular level and the positively enriched pathways, operons, and regulons data are helpful in understanding the resistance patterns in Mtb. The upregulated genes during the exposure of Bedaquiline and Capreomycin can be considered as potent drug targets for the development of new anti-TB drugs.

Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification.

Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1-7 and BNTZ 8-13). The study aims to carry out the development of benzothiazole based anti-TB compounds. Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method. It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 µg/mL and 11 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies. To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.

A genomic analysis of Mycobacterium immunogenum strain CD11_6 and its potential role in the activation of T cells against Mycobacterium tuberculosis

BackgroundMycobacterium tuberculosis (Mtb) is an etiological agent of tuberculosis (TB). Tuberculosis is a mounting problem worldwide. The only available vaccine BCG protects the childhood but not adulthood form of TB. Therefore, efforts are made continuously to improve the efficacy of BCG by supplementing it with other therapies. Consequently, we explored the possibility of employing Mycobacterium immunogenum (Mi) to improve BCG potential to protect against Mtb.ResultsWe report here the genome mining, comparative genomics, immunological and protection studies employing strain CD11_6 of Mi. Mycobacterium immunogenum was isolated from duodenal mucosa of a celiac disease patient. The strain was whole genome sequenced and annotated for identification of virulent genes and other traits that may make it suitable as a potential vaccine candidate. Virulence profile of Mi was mapped and compared with two other reference genomes i.e. virulent Mtb strain H37Rv and vaccine strain Mycobacterium bovis (Mb) AFF2122/97. This comparative analysis revealed that Mi is less virulent, as compared to Mb and Mtb, and contains comparable number of genes encoding for the antigenic proteins that predict it as a probable vaccine candidate. Interestingly, the animals vaccinated with Mi showed significant augmentation in the generation of memory T cells and reduction in the Mtb burden.ConclusionThe study signifies that Mi has a potential to protect against Mtb and therefore can be a future vaccine candidate against TB.

Characterisation of genes differentially expressed in macrophages by virulent and attenuated Mycobacterium tuberculosisthrough RNA-Seq analysis

Tuberculosis (TB) remains a global healthcare issue. Understanding the host-pathogen interactions in TB is vital to develop strategies and therapeutic tools for the control of Mycobacterium tuberculosis (Mtb). In this study, transcriptome analyses of macrophages infected with either the virulent Mtb strain H37Rv (Rv) or the avirulent Mtb strain H37Ra (Ra) were carried out and 750 differentially expressed genes (DEGs) were identified. As expected, the DEGs were mainly involved in the induction of innate immune responses against mycobacterial infections. Among the DEGs, solute carrier family 7 member 2 (Slc7a2) was more strongly expressed in Ra-infected macrophages. Induction of SLC7A2 was important for macrophages to control the intracellular survival of Mtb. Our results imply that SLC7A2 plays an important role in macrophages during Mtb infection. Our findings could prove useful for the development of new therapeutic strategies to control TB infection.

Resazurin Assay Data for Mycobacterium tuberculosis Supporting a Model of the Growth Accelerated by a Stochastic Non-Homogeneity

Tuberculosis is one of the most widespread worldwide diseases heavily affecting society. Among popular modern laboratory tests for mycobacterial growth, the resazurin assay has certain advantages due to its effectiveness and relatively low cost. However, the high heterogeneity of the mycobacterial population affects the average growth rate. This fact must be taken into account in a quantitative interpretation of these tests’ output—fluorescence growth curves—related to the population growth of viable mycobacteria. Here, we report the spectrophotometric data obtained via the resazurin assay for the standard reference strain of Mycobacterium tuberculosis H37Rv for different initial dilutions and generation numbers of the culture, as well as their primary processing from the point of view of the stochastic multiplicative growth model. The obtained data, which indicate an accelerated (instead of linear) growth of the population density logarithm between the end of the lag phase and the saturation, provide evidence of the importance of the growth rates’ stochasticity. An analysis of the curve fits resulted in an estimation of the first two moments of the growth rates’ probability distributions, showing its relevance to vital processes for mycobacterial culture.

Expansion of a novel lead targeting M. tuberculosis DHFR as antitubercular agents.

A series of 1-(1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indol-3-yl)ethanone and ethyl 1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indole-3-carboxylate derivatives were designed based on bioisosteric replacement of previously reported antitubercular agent (IND-07). Twenty ligands were successfully synthesized and some of them were found to have good in vitro activity (MIC < 10 μM) against the H37Rv strain of Mycobacterium tuberculosis. Among these compounds, KC-08 and KC-11 inhibited Mtb-DHFR with 4- and 18-fold selectivity for Mtb-DHFR over h-DHFR, respectively. Compound KC-11 display acceptable ADME, and better pharmacokinetic profiles than IND-07. Docking studies were performed to predict the binding mode of the compounds within the active site of Mtb-DHFR and h-DHFR. The results of our study suggest that compound KC-11 may serve as a valuable lead for the design and development of selective inhibitors of Mtb-DHFR with potential therapeutic application in tuberculosis.

Molecular hybridization approach for phenothiazine incorporated 1,2,3-triazole hybrids as promising antimicrobial agents: Design, synthesis, molecular docking and in silico ADME studies

The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 μg/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads.

Pyridine and nitro-phenyl linked 1,3,4-thiadiazoles as MDR-TB inhibitors

In the present study, a series of substituted 1,3,4-thiadiazole derivatives 4(a–o), 5(a–m) and 6(a–j) were synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectroscopic technique. The synthesized compounds were evaluated for their in vitro anti-mycobacterial activity against the Mycobacterium tuberculosis H37Rv and resistance MDR-TB strain. Among the compounds tested N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)furan-2-carboxamide (4h) showed significant inhibitory activity with MIC of 9.87 μM (H37Rv strain) and 9.87 μM (MDR-TB strain) compared to isoniazide [MIC of 3.64 μM (H37Rv) and >200 μM (MDR-TB strain)] and rifampin [MIC of 0.152 μM (H37Rv) and 128 μM (MDR-TB strain)]. In addition, these compounds have also been assessed for their cyto-toxicity to a mammalian Vero cell line using the MTT assay. The result shows that these compounds exhibit anti-tubercular activity at non-cytototoxic concentrations.

Discovery of meta-Amido Bromophenols as New Antitubercular Agents.

A series of meta-amido bromophenol derivatives were designed and synthesized. The compounds were found to potently inhibit the growth of Mycobacterium tuberculosis H37Ra. They also exhibited moderate inhibitory activity against Mycobacterium tuberculosis H37Rv and multidrug-resistant strains. The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. Moderate cytotoxicities and good metabolic stability were observed for the selected compounds. The results demonstrated meta-amido bromophenols as a new class of antitubercular agents with good potentials.

Immunotherapeutic effects of recombinant adenovirus encoding interleukin 12 in experimental pulmonary tuberculosis.

High dose of Mycobacterium tuberculosis (Mtb) strain H37Rv administered by intratracheal injection in BALB/c mice induce progressive tuberculosis (TB). In this model, during the first month there is a temporal control of bacillary growth, in coexistence with macrophage activation, granuloma formation and Th-1 response. Then, bacterial proliferation recommences, accompanied by progressive pneumonia and decreasing expression of protective cytokines (IFN-γ and TNF-α). In this model, we studied the IL-12 gene expression kinetics and cellular source. There is a rapid and progressive IL-12 expression peaking at day 14, when granulomas start their formation and numerous macrophages show strong IL-12 immunostaining, while during progressive TB there is a significant decrease of IL-12 expression and occasional macrophages showed IL-12 immunolabeling. In the second part of this study, we determined the immunotherapeutic effect of recombinant adenoviruses that codify IL-12 (AdIL-12). Intratracheal administration of only one dose of AdIL-12 one day before Mtb infection produced significant decrease of bacterial loads, lesser pneumonia and higher expression of TNF-α, IFN-γ and iNOS. When only one dose of AdIL-12 was given in healthy mice cohoused with infected mice with highly virulent and transmissible Mtb, total prevention of infection was conferred. Moreover, when AdIL-12 was administered by intranasal route in animals suffering late active TB after 2months of infection, a very low pulmonary bacilli burdens was detected. These experimental data confirm that IL-12 is a significant cytokine in the immune protection against Mtb, and gene therapy based in adenoviruses coding this cytokine increased protective immunity and prevent Mtb transmission.

Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties

We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MIC < 0.25 μM). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 μM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.