Resistant Tuberculosis Strains Research Articles

Increasing circulation of multi-drug resistant tuberculosis strains in Buryatia, high-burden and ethnically diverse region in the Russian Far East

Buryatia is a multidrug-resistant tuberculosis (MDR-TB) high-burden region in the Russian Far East with ethnically diverse population (30 % Mongoloid Buryats and 65 % Russians). Two hundred M. tuberculosis strains from newly-diagnosed patients were subjected to phenotypic testing and genotyping. The Beijing genotype was more prevalent among Russians than Buryats (68 % vs 53 %; P = 0.055). European non-Beijing genotypes (LAM, Ural, Haarlem) were double more prevalent in Buryats vs Russians (39.2 % vs 20.5 %; P = 0.01). Higher prevalence of Beijing among former prison inmates (79 % vs 61 % in other patients, P = 0.1) suggests its increased transmissibility. The Russian epidemic cluster B0/W148 was in 9.5 %, double smaller than elsewhere in Siberia. The hypervirulent Beijing 14717-15-cluster was endemic in Buryatia but paradoxically enough, it was more frequently isolated from Russians than Buryats (9.1 % vs 3.9 %; P = 0.2). Beijing subtypes B0/W148, CAO, and 14717-15 were associated with poly/multi-drug resistance (P = 0.01–0.0001). HIV coinfection was more frequent in Russians than in Buryats: 35/141 (24.8 %) vs 5/51 (9.8 %), P = 0.03. To conclude, M. tuberculosis population structure in Buryatia retained its singularities compared to other parts of Russia and remains strikingly different from the neighboring Mongolia. A circulation of strongly MDR-associated Beijing subtypes and drug-resistant non-Beijing strains highlights a risk of their broader dissemination.

Development of multi-epitope based subunit vaccine against Mycobacterium Tuberculosis using immunoinformatics approach

The etiological agent of tuberculosis (TB), Mycobacterium tuberculosis, is a deadly pathogen that adapts to thrive within the host. Since 2020, the COVID-19 pandemic has had colossal health, societal, and economic consequences, which have affected the reporting of new incidences and mortality cases of TB. As per the WHO 2022 report, 10.6 million people were diagnosed with TB, and 1.6 million died worldwide. The increase in resistant strains of tuberculosis is making it more burdensome to reach the End TB strategy. A reliable and efficient TB vaccine that may avert both primary infection and recurrence of latent TB in adults and adolescents is of the utmost importance. In this study, we used computational techniques to predict the ability of HLA molecules to display epitopes for six TB proteins (PPE68, PE_PGRS17, EspC, LDT4, RpfD, and RpfC) to design the multi-epitope subunit vaccine. From the aimed proteins, the potential B-cell, helper T lymphocyte (HTL), and cytotoxic T lymphocyte (CTL) epitopes were predicted and linked together with LPA adjuvant, and the vaccine was designed. The vaccine’s physicochemical analysis demonstrates that it is non-allergic, non-toxic, and antigenic. Then, the vaccine structure was predicted, improved, and verified to yield the optimal structure. The developed vaccine’s binding mechanism with distinct immunogenic receptors (Tlr2 and MHC-II) was assessed utilizing molecular docking. The molecular dynamic simulation and MMPBSA analysis were performed to comprehend the complexes’ dynamics and stability. The immune simulation was utilized to anticipate the vaccine’s immunogenic attributes. In silico cloning was employed to demonstrate the efficient expression of the designed vaccine in E. coli as a host. Moreover, in vitro and in vivo animal testing is required to determine the efficacy of the in silico developed vaccine. Communicated by Ramaswamy H. Sarma

Chromatography fractions from the ethyl acetate fraction of Harungana madagascariensis Lam. Ex Poiret fruits (Hypericaceae) inhibited the growth of Mycobacterium tuberculosis

The economic burden of drug resistant tuberculosis strain is enormous due to its being one of the leading cause of global mortality. New treatments that are faster, simpler and affordable are urgently needed. Thus this research aimed to validate that the ethyl acetate fraction from the Nigeria variety of Harungana madagascariensis contain secondary metabolites with anti-Mycobacterium tuberculosis activity. The fruit of H. madagascariensis was extracted with 70% aqueous ethanol by cold maceration. The crude aqueous ethanol extract was defatted with n-hexane by partitioning and the aqueous portion further partitioned with ethyl acetate to give ethyl acetate portion (EAP) used in this study. Fractionation of EAP was done using chromatographic techniques. Phytochemical screening of the fractions was done using standard methods. Anti- Mycobacterium tuberculosis screening was done using Lowestein Jensen(LJ) method (test fractions stock solution 1mg/ml diluted to a 0.01mg/ml in the LJ medium while isoniazid, dihydrostreptomycin, ethambutol and rifampicin at their reported minimum inhibition concentrations(MIC) were used as reference anti-TB drugs). Four (4) chromatography fractions (EAF1 –EAF4) were obtained. All fractions were found to contain phenolics with anthraquinone present in EAF2 and EAF3. Fractions EAF3 and EAF4 inhibited the growth of the Mycobacteria tuberculosis. This preliminary screening validates the use of H. madagascariensis in traditional medicine and as a potential source of natural products with anti-Mycobacterium tuberculosis activity as well as a good source of anthraquinone.

C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol.

The emergence of extensively drug-resistant strains of Mycobacterium tuberculosis threatens decades of progress in the treatment of a disease which remains one of the leading infectious causes of death worldwide. The development of novel antimycobacterial compounds is therefore essential to reinforce the existing antitubercular drug discovery pipeline. There is also interest in new compounds which can synergize with existing antitubercular drugs and can be deployed as part of a combination therapy. This strategy could serve to delay the emergence of resistance to first-line anti-tuberculosis drugs and increase their efficacy against resistant strains of tuberculosis. Previous research has established that several C-1 substituted tetrahydroisoquinolines have antimycobacterial activity. Here we sought to expand our understanding of their antimycobacterial structure activity relationships and their potential to act as adjunct therapies alongside existing antitubercular drugs. Three chemical series were synthesised and assayed for their antimycobacterial potency, mammalian cell toxicity, inhibition of whole-cell efflux and synergism with isoniazid, rifampicin, and ethambutol. Several compounds were found to inhibit the growth of mycobacteria. Potent inhibitors of whole-cell efflux were also identified, as well as compounds which exhibited synergism with rifampicin and ethambutol. Structure-activity relationships were identified for antimycobacterial potency, improved selectivity, whole cell efflux inhibition and synergism. Potent whole-cell efflux inhibitors and synergistic compounds were identified, suggesting potential development as adjuncts to existing anti-tuberculosis chemotherapy.

MDR-TB in Pakistan: Challenges, efforts, and recommendations

Tuberculosis (TB), a global health concern is also a leading cause of mortality and morbidity across Pakistan affecting a major proportion of the population. The absence of an integrated system to control the spread of TB has led to a rise in multidrug resistant strains of TB (MDR-Tb) which do not exhibit any sensitivity towards the first line therapy for TB. Such adverse circumstances call for effective planning strategies to mitigate the health hazards of MDR-TB. This article briefly highlights the challenges encountered by the already burdened healthcare system and suggests relatively inexpensive approaches to tackle the ongoing crisis associated with MDR-TB on a national scale.

Shikimate Kinase; Searching for Potential Novel Anti‐Tubercular Agents

Tuberculosis is a respiratory infection with over 10 million reported cases each year. This infection rate is responsible for over two million deaths annually, second only to HIV in fatalities among infectious diseases annually. Studies in the last decade have shown that tuberculosis rates have gradually increased. This observation suggests that there is an alarming increase in the prevalence of drug resistant strains of tuberculosis, thus the need for the discovery of novel antitubercular agents. The shikimate pathway is a seven step metabolic route that produces aromatic amino acids and other cellular metabolites. The target enzyme in this project, Mycobacterium tuberculosis Shikimate Kinase (MtSK), catalyzes the 5th step of this pathway. MtSK converts shikimate to shikimate 3 phosphate. The overall goal of this project is to express and characterize MtSK to screen for potential antitubercular agents. Initial methods included a bacterial transformation of XL1 blue competent E.coli cells. This preliminary transformation was performed using a pET‐21b plasmid with an aroK gene inserted into the multiple cloning site. Successfully transformed XL1 blue cells were cloned and a second transformation of BL21 DE3 competent cells was performed. Initial small scale expression showed the presence of a band around 20 kDa. The theoretical mass of the enzyme is 19.6 kDa which suggests MtSK was successfully expressed. Expression analysis for large scale supported data from small scale as a band of 20 kDa was present. The purity and molecular weight of MtSK were confirmed by nickel affinity chromatography as well as ESI‐LC‐MS. ATP‐dependent kinetic parameters determined via a spectrophotometric coupled assay showed a kcat of 50 ± 6 mM, KM of 0.2 ± 0.04 mM. shikimate dependent kinetic parameters showed a kcat of 55 ± 2 mM, KM of 1.8 ± 0.1 mM. Quenching intrinsic tyrosine fluorescence showed binding affinities similar to ATP and shikimate‐dependent parameters. The marine compound, avarone showed substantial quenching of intrinsic fluorescence. The inhibitory mechanism of avarone on MtSK is currently under investigation.

Alterations in molecular response of Mycobacterium tuberculosis against anti-tuberculosis drugs.

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, has plagued humans since the early middle-ages. More than one million deaths are recorded annually due to TB, even in present times. These deaths are primarily attributed to the constant appearance of resistant TB strains. Even with the advent of new therapeutics and diagnostics techniques, tuberculosis remains challenging to control due to resistant M. tuberculosis strains. Aided by various molecular changes, these strains adapt to stress created by anti-tuberculosis drugs. The review thus is an overview of ongoing research in the genome and transcriptome of antibiotic-resistant TB. It explores omics-based research to identify mutation and utilization of differential gene expression. This study shows several mutations distinctive in the first- and second-line drug-resistant M. tuberculosis strains. It also explores the expressional differences of genes involved in the fundamental process of the cells and how they help in drug resistance. With the development of transcriptomics-based studies, a new insight has developed to inquire about gene expression changes in drug resistance. This information on expressional pattern changes can be utilized to design the basic platform of anti-TB treatments and therapeutic approaches. These novel insights can be instrumental in disease diagnosis and global containment of resistant TB.

Distribution patterns of drug resistance Mycobacterium tuberculosis among HIV negative and positive tuberculosis patients in Western Kenya

Distribution patterns of drug resistance Mycobacterium tuberculosis among HIV negative and positive tuberculosis patients in Western Kenya

Using Virtual Screening to Identify Novel Inhibitors for Enoyl‐Acyl Carrier Protein Reductase in Mycobacterium tuberculosis

Mycobacterium tuberculosis causes the highly infectious disease Tuberculosis, an airborne illness primarily affecting the lung which still remains in the top 10 causes of death worldwide, largely due to recent antibiotic resistant tuberculosis strains. InhA, the enoyl-acyl carrier protein reductase, is an advantageous drug target due to its essentiality in M. tuberculosis, as it catalyzes the enoyl-acyl carrier protein double bond reduction. This reaction is an essential precursor to create mycolic acids for cell wall fatty acid biosynthesis. Although there are current antibiotics for this enzyme, many of these once-effective treatments are losing efficacy to the antibiotic-resistant strains, creating a need for novel InhA inhibitors. Using an MtInhA crystallography structure (PDB 4DRE), numerous large libraries of compounds were virtually screened against InhA using the virtual screening program GOLD, Genetic Optimization for Ligand Docking (CCDC). This program uses a genetic algorithm to predict and quantify the binding interactions to estimate the ligand's total binding energy with a relative binding score for each. First, control ligands were docked to validate the GOLD software for compounds known to inhibit MtInhA. After a preliminary screening of tens of thousands of chemical compounds from various libraries was run with a low thoroughness to quickly screen out low-probability hits for MtInhA, the top ten percent of ligands were then screened with higher thoroughness in GOLD, along with additional screening in the programs VINA and ICM. Supplemental filtering using Lipinski's criteria and examination of the best-scoring ligands in the visualization program PyMOL further narrowed down the list. The majority of these top hits were found in the chemical library Novacore, along with a few ligands in the CBZinc library. Novacore's library greatly exceeded the best control ligand scoring 110.93, with scores ranging from 160.09 to 64.4. CBZinc's scores produced a much wider range of scores, from 110.47 to 24.75. These libraries have starkly different binding methods for MtInhA, with Novacore's ligands creating strong binding through a few strong interactions to a small portion of the active site, while CBZinc's ligands create strong binding through numerous interactions which span the entire active site. While the conformations differ greatly, these compounds are noteworthy nonetheless and should be further tested for MtInhA inhibition through wet-lab research.

Evaluating bedaquiline as a treatment option for multidrug-resistant tuberculosis

ABSTRACT Introduction: Despite efforts to the contrary, tuberculosis remains one of the leading causes of death in the world. The appearance of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis has increased the need for new therapeutic options against these strains. Areas covered: This review covers the in vitro susceptibility, pharmacokinetics, and pharmacodynamics of bedaquiline, a new drug shown to be active against M. tuberculosis-resistant strains. The authors further review clinical data concerning its use against MDR and XDR strains, discussing recent clinical guidelines from different international societies. Expert opinion: Available data demonstrate the usefulness of bedaquiline against resistant M. tuberculosis. Despite the difficulty in analyzing multidrug therapies, the use of bedaquiline in MDR and XDR tuberculosis increases success rates, allowing shortened treatments and lower drug use than previously recommended regimens. Moreover, the fact that MDR and XDR strains are common in many places creates a need to include this drug in the currently available protocols. It is essential to overcome the substantial barriers that some countries encounter in obtaining bedaquiline, as doing so will make therapeutic regimens including this drug available for all patients.

Use of whole genome sequencing to identify transmission of resistant tuberculosis strains in italy

Aims and objectives: In the present study, we report on the cross-border clusters involving Italian MDR-TB strains collected in the framework of the ECDC supported EUSeqMyTB project. This pilot study was conducted as retrospective/prospectic WGS-based surveillance project to monitor possible cross-border TB transmission involving strains isolated in Europe. Methods: Within the EUSeqMyTB study period (approximately 24 months) 2218 RR/MDR-TB strains from 25 EU countries were collected, including a total of 127 strains from Italy. Additional RR/MDR-TB strains were collected and sequenced in Italy as part of the national WGS-based surveillance. All strains were subjected to WGS according to standard protocol for the Ion torrent or Illumina platform. Sequencing of Italian strains was performed by Illumina. WGS data were subjected to quality check (See Tagliani et al ERJ 2020) and analysis was performed by SNP based pipeline and Core Genome MSLT (SeqSphere+ Redom GmbH, Germany) Results: The Euroamerican superlineage was the most represented in Italy (64% of cases). The Italian strains were included in the 3 major cross-border clusters identified in the study. The largest cluster comprised a total of 30 patients from 3 different countries, including 22 individuals born in the same European country. Italy contributed to this cluster with 12 cases isolated during the study period and with additional two cases after the end of the study in 2019. The clustered strains isolated in Italy were from both Italian born and foreign born TB cases, the majority of which were from another EU country. For the majority of the clustered cases isolated in Italy the epidemiological link was identified and the cluster was linked to a pub located in Milan, Italy. A subgroup of the MDR-TB cases showed additional resistance to 2nd line anti TB drugs as well as resistance to bedaquiline (linked to a large deletion in the rv0678 gene). One clustered case showed also a minimum inhibitory concentration for delamanid close to the drug critical concentration. For the additional two large cross-border clusters identified in the EUSeqMyTB pilot study, Italy contributed with respectively 2 and 5 cases. All of them were linked to migration from sub-Saharan Africa countries and no case of transmission to Italian born population was identified neither during the study timeframe nor afterwards. Conclusions: We documented that WGS-based surveillance of RR/MDR-TB strains highly support contact tracing investigation. The implementation of WGS in routine should require the performance of WGS as soon as the strain become available and not in batches with delay. Information exchange with neighboring countries should be facilitate. We report on an ongoing transmission of a pre-XDR strain linked to a larger EU cluster and that the transmitted strain is highly resistant to therapy with the current MDR recommended treatment.

Small organic molecules targeting the energy metabolism of Mycobacterium tuberculosis.

Causing approximately 10 million incident cases and 1.3-1.5 million deaths every year, Mycobacterium tuberculosis remains a global health problem. The risk is further exacerbated with latent tuberculosis (TB) infection, the HIV pandemic, and increasing anti-TB drug resistance. Therefore, unexplored chemical scaffolds directed towards new molecular targets are increasingly desired. In this context, mycobacterial energy metabolism, particularly the oxidative phosphorylation (OP) pathway, is gaining importance. Mycobacteria possess primary dehydrogenases to fuel electron transport; aa3-type cytochrome c oxidase and bd-type menaquinol oxidase to generate a protonmotive force; and ATP synthase, which is essential for both growing mycobacteria as well as dormant mycobacteria because ATP is produced under both aerobic and hypoxic conditions. Small organic molecules targeting OP are active against latent TB as well as resistant TB strains. FDA approval of the ATP synthase inhibitor bedaquiline and the discovery of clinical candidate Q203, which both interfere with the cytochrome bc1 complex, have already confirmed mycobacterial energy metabolism to be a valuable anti-TB drug target. This review highlights both preferable molecular targets within mycobacterial OP and promising small organic molecules targeting OP. Progressive research in the area of mycobacterial OP revealed several highly potent anti-TB compounds with nanomolar-range MICs as low as 0.004μM against Mtb H37Rv. Therefore, we are convinced that targeting the OP pathway can combat resistant TB and latent TB, leading to more efficient anti-TB chemotherapy.

Nanotechnology‐Based Targeted Drug Delivery: An Emerging Tool to Overcome Tuberculosis

AbstractThe appearance and rapid spread of drug resistant strains of tuberculosis (TB), one of the deadliest infectious diseases, pose a serious threat to public health and increase the need for shorter, less toxic, and more effective therapies. Developing new drugs is difficult and often associated with side effects, so nanotechnology has emerged as a tool to improve current treatments and to rescue drugs having elevated toxicity or poor solubility. Due to their size and surface chemistry, antimicrobial‐loaded nanocarriers are avidly taken up by macrophages, the main cells hosting Mycobacterium tuberculosis. Macrophages are continuously recruited to infected areas, they can transport drugs with them, making passive targeting a good strategy for TB treatment. Active targeting (decorating surface of nanocarriers with ligands specific to receptors displayed by macrophages) further increases local drug concentration, and thus treatment efficacy. Although in in vivo studies, nanocarriers are often administered intravenously in order to avoid inaccurate dosage in animals, translation to humans requires more convenient routes like pulmonary or oral administration. This report highlights the importance and progress of pulmonary administration, passive and active targeting strategies toward bacteria reservoirs to overcome the challenges in TB treatment.

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives.

Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are a limited number of medications available to treat TB; additionally, multi-drug resistant TB and extensively-drug resistant TB strains are becoming more prevalent. As a result of various factors, such as increased costs of developing new medications and adverse side effects from current medications, researchers continue to evaluate natural compounds for additional treatment options. These substances have the potential to target bacterial cell structures and may contribute to successful treatment. For example, a study reported that green and black tea, which contains epigallocatechin gallate (a phenolic antioxidant), may decrease the risk of contracting TB in experimental subjects; cumin (a seed from the parsley plant) has been demonstrated to improve the bioavailability of rifampicin, an important anti-TB medication, and propolis (a natural substance produced by honeybees) has been shown to improve the binding affinity of anti-TB medications to bacterial cell structures. In this article, we review the opportunistic pathogen M. tuberculosis, various potential therapeutic targets, available therapies, and natural compounds that may have anti-TB properties. In conclusion, different natural compounds alone as well as in combination with already approved medication regimens should continue to be investigated as treatment options for TB.

Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory

Conventional drugs used to treat Tuberculosis (TB) are becoming ineffective due to the occurrence of multiple drug resistant strains of tuberculosis (TB). This has made the TB disease a a serious global health dilemma. Hence, there is desperate necessity for the advancement of new drugs. In this work, the chemical reactivity and bioactivity of several analogs ofpyrazinamide (PZA) were investigated. PZA is one of the first-line of drugs used to treat tuberculosis and is a key contributor to shortening the treatment time for the disease. Chemical reactivity descriptors of pyrazinamide (PZA) and its analogs of acetylsalicyclic acid and salicyclic acid were investigated using conceptual density functional theory in water as a solvent at the MN12SX/Def2TZVP level of theory. Results have shown that all PZA analogs have improved their global and local reactivity indeces as compared to pyrazinamide based on its electronegativity, electrodonating power, electroaccepting power, eletrophilicity, global hardness and dual descriptor condensed fukui indexes. Moreover, their pKa values are slightly higher than PZA. In terms of its drug-likeness, all PZA analogs passed the Lipinski's Rule of Five criteria. Furthermore, their bioactivity scores are significantly better than pyrazinamide indicating good reaction to G-Protein Coupled Receptor (GPCR) ligands, kinase inhibitors, ion channel modulators, nuclear receptor ligands, protease inhibitors and other enzyme targets. Overall, the PZA analogs are found to be promising anti-tuberculosis drugs. Based on global and local reactivity descriptors, pKa and bioactivity scores, PZA analog of 5-n-Octanoylsalicylic acid is the most reactive among the PZA analogs tested.

Light Forge: A Microfluidic DNA Melting-based Tuberculosis Test.

BackgroundThere is a well-documented lack of rapid, low-cost tuberculosis (TB) drug resistance diagnostics in low-income settings across the globe. It is these areas that are plagued with a disproportionately high disease burden and in greatest need of these diagnostics.MethodsIn this study, we compared the performance of Light Forge, a microfluidic high-resolution melting analysis (HRMA) prototype for rapid low-cost detection of TB drug resistance with a commercial HRMA device, a predictive “nearest-neighbor” thermodynamic model, DNA sequencing, and phenotypic drug susceptibility testing (DST). The initial development and assessment of the Light Forge assay was performed with 7 phenotypically drug resistant strains of Mycobacterium tuberculosis (M.tb) that had their rpoB gene subsequently sequenced to confirm resistance to Rifampin. These isolates of M.tb were then compared against a drug-susceptible standard, H37Rv. Seven strains of M.tb were isolated from clinical specimens and individually analyzed to characterize the unique melting profile of each strain.ResultsLight Forge was able to detect drug-resistance linked mutations with 100% concordance to the sequencing, phenotypic DST and the “nearest neighbor” thermodynamic model. Researchers were then blinded to the resistance profile of the seven M.tb strains. In this experiment, Light Forge correctly classified 7 out of 9 strains as either drug resistant or drug susceptible.ConclusionsLight Forge represents a promising prototype for a fast, low-cost diagnostic alternative for detection of drug resistant strains of TB in resource constrained settings.

Pulmonary tuberculosis caused by Mycobacterium tuberculosis resistant strains and the electronic platform for formation of the treatment regimens

Pulmonary tuberculosis caused by Mycobacterium tuberculosis resistant strains and the electronic platform for formation of the treatment regimens

Population structure of drug-resistant Mycobacterium tuberculosis in Central Asia

BackgroundDrug-resistant tuberculosis (TB) is a major public health concern threathing the success of TB control efforts, and this is particularily problematic in Central Asia. Here, we present the first analysis of the population structure of Mycobacterium tuberculosis complex isolates in the Central Asian republics Uzbekistan, Tajikistan, and Kyrgyzstan.MethodsThe study set consisted of 607 isolates with 235 from Uzbekistan, 206 from Tajikistan, and 166 from Kyrgyzstan. 24-loci MIRU-VNTR (Mycobacterial Interspersed Repetitive Units - Variable Number of Tandem Repeats) typing and spoligotyping were combined for genotyping. In addition, phenotypic drug suceptibility was performed.ResultsThe population structure mainly comprises strains of the Beijing lineage (411/607). 349 of the 411 Beijing isolates formed clusters, compared to only 33 of the 196 isolates from other clades. Beijing 94–32 (n = 145) and 100–32 (n = 70) formed the largest clusters. Beijing isolates were more frequently multidrug-resistant, pre-extensively resistant (pre-XDR)- or XDR-TB than other genotypes.ConclusionsBeijing clusters 94–32 and 100–32 are the dominant MTB genotypes in Central Asia. The relative size of 100–32 compared to previous studies in Kazakhstan and its unequal geographic distribution support the hypothesis of its more recent emergence in Central Asia. The data also demonstrate that clonal spread of resistant TB strains, particularly of the Beijing lineage, is a root of the so far uncontroled MDR-TB epidemic in Central Asia.

TB or not TB? That is the question regarding TB treatment in a remote provincial hospital in Solomon Islands.

Tuberculosis (TB) remains a significant public health challenge in Solomon Islands. Limited healthcare resources, geography, and sociocultural beliefs, coupled with lack of laboratory diagnostic tools, leads to diagnostic and treatment outcome uncertainty. Kirakira Hospital (KKH) is the main provincial hospital of Makira-Ulawa Province in Solomon Islands. A retrospective clinical audit of hospitalised TB patients in KKH over a 2-year period between July 2015 and July 2017 was conducted. The cost of TB treatment was estimated by calculating the total number of inpatient bed days of treatment. Data were available for 42 of 78 listed TB patients including 23 males and 19 females, and 9 children aged less than 16 years. The average age was 35 years (range 9 months - 74 years). Thirty-five of these received a chest X-ray. All patients had at least one of the following: fever, night sweats, chronic cough and haemoptysis as part of their clinical TB presentation. Thirty-six completed the full 8-week duration of intensive HRZE treatment as inpatients of KKH. The audit shows the treatment of TB consumes 15% of the current healthcare budget of Makira-Ulawa Province. TB remains a common clinical diagnosis in KKH. TB consumes 15% of the current healthcare budget of Makira-Ulawa Province. The limited capacity and data about the management of TB in Makira province mean that it is not currently possible to measure if there has been any progress towards eradicating TB in Solomon Islands. Laboratory investigations for TB available in Makira including sputum analysis and the GeneXpert are required to improve the accuracy of diagnosis and identify multidrug resistant strains of TB. This needs to be coupled with robust monitoring and data collection of both inpatients and outpatients to ensure the current treatment protocols for TB are being followed in Makira-Ulawa Province. These steps are essential if TB is to be eradicated from the provinces of Solomon Islands by 2030.

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.