Resistant Strains Of Mycobacterium Tuberculosis Research Articles

A robust computational quest: Discovering potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis.

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through invitro and invivo experiments.

Phenotypic and Genotypic Drug Resistance of Mycobacterium tuberculosis Strains Isolated from HIV-Infected Patients from a Third-Level Public Hospital in Mexico.

Drug-resistant tuberculosis (TB) is associated with higher mortality rates in patients with human immunodeficiency virus (HIV). In Mexico, the number of deaths due to TB among the HIV-positive population has tripled in recent years. Ninety-three Mycobacterium tuberculosis strains isolated from the same number of HIV-infected patients treated in a public hospital in Mexico City were studied to determine the drug resistance to first- and second-line anti-TB drugs and to identify the mutations associated with the resistance. Of the 93 patients, 82.7% were new TB cases, 86% were male, and 73% had extrapulmonary TB. Most patients (94%) with a CD4 T-lymphocyte count <350 cells/mm3 were associated with extrapulmonary TB (p <0.0001), whilst most patients (78%) with a CD4 T-lymphocyte count >350 cells/mm3 were associated with pulmonary TB (p = 0.0011). Eighty-two strains were pan-susceptible, four mono-resistant, four poly-resistant, two multidrug-resistant, and one was extensively drug-resistant. In the rifampicin-resistant strains, rpoB S531L was the mutation most frequently identified, whereas the inhA C15T and katG S315T1 mutations were present in isoniazid-resistant strains. The extensively drug-resistant strain also contained the mutation gyrA D94A. These data highlight the need to promptly diagnose the drug resistance of M. tuberculosis among all HIV-infected patients by systematically offering access to first- and second-line drug susceptibility testing and to tailor the treatment regimen based on the resistance patterns to reduce the number of deaths in HIV-infected patients.

Molecular epidemiology and drug resistance of Mycobacterium tuberculosis in a tertiary care hospital in northeastern Mexico.

Tuberculosis (TB) is a re-emerging disease considered a public health concern. In the present study, we analyzed the epidemiology and drug resistance of Mycobacterium tuberculosis strains isolated from patients with pulmonary TB. Mycobacterium tuberculosis isolates (n = 190) were obtained from patients with pulmonary TB admitted to Dr. José Eleuterio González University Hospital (UH). Each M. tuberculosis isolate was analyzed by spoligotyping (spacer oligonucleotide typing) and MIRU-VNTR (Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat). Drug resistance was evaluated using the Anyplex™ II MTB/MDR/XDR assay. The predominant spoligotypes observed were X1 (SIT 119, n = 46), T1 (SIT 53, n = 40), H3 (SIT 50, n = 13), Beijing (SIT 1, n = 11), and EAI2-Manila (SIT 19, n = 8). MIRU-VNTR analysis showed that the locus QUB-26 had the highest allelic variability. The observed drug resistance included monoresistance to rifampicin (2.6%; n = 5), isoniazid (3.2%; n = 6), and fluoroquinolones (1.6%; n = 3) as well as multidrug resistance (5.3%; n = 10). All of the Beijing strains were susceptible. Regarding comorbidities, 13.7% (26/190) of the patients were co-infected with TB and HIV (TB+HIV+), and 31.6% (55/190) had TB along with diabetes (TB + diabetes). The most prevalent lineages were X1 (SIT 119; 24.3%) and T1 (SIT 53; 21%). An alarming proportion (12.6%) of M. tuberculosis isolates presented drug resistance. To effectively manage TB, continuous surveillance of regional strain dissemination, drug resistance profiles, and TB-associated comorbidities is crucial.

Chemoinformatics approach to the screening and development of quassinoids from Brucea javanica as antituberculosis drugs

Background: The morbidity and mortality of tuberculosis (TB) remain high in various countries as a result of pharmacological intervention failures, such as incomplete treatment regimens and inadequate doses, triggering resistance of Mycobacterium tuberculosis strains to anti-TB drugs used. This phenomenon requires innovation to explore and develop novel anti-TB drugs so that the problem of resistance is overcome and treatment of TB is more optimal. Objective: In this study, chemoinformatics investigations were carried out on quassinoids derived from Brucea javanica to be developed as anti-TB drugs. Method: Evaluation of drug-likeness with the SwissADME online tool, prediction of toxicity with the pkCSM online tool, and molecular docking studies with AutoDock Vina software were performed on 18 quassinoids from Brucea javanica. Result: The findings showed that Bruceine A, Bruceine, and Bruceine D, met the drug-likeness criteria, showed a good toxicity profile, and had better binding energy (-7.5; -7.5; and -7 kcal/mol, respectively) than isoniazid (-5.8 kcal/mol) which is a first-line anti-TB drug on enoyl acyl carrier protein reductase (InhA; PDB ID: 2NSD). Conclusion: This study found several quassinoids from Brucea javanica with the potential to be developed as anti-TB drugs.

Characterisation and development of histopathological lesions in a guinea pig model of Mycobacterium tuberculosis infection.

Tuberculosis (TB) remains a very significant infectious disease worldwide. New vaccines and therapies are needed, even more crucially with the increase of multi-drug resistant Mycobacterium tuberculosis strains. Preclinical animal models are very valuable for the development of these new disease control strategies. Guinea pigs are one of the best models of TB, sharing many features with the pathology observed in human TB. Here we describe the development of TB lesions in a guinea pig model of infection. We characterise the granulomatous lesions in four developmental stages (I-IV), using histopathological analysis and immunohistochemical (IHC) techniques to study macrophages, T cells, B cells and granulocytes. The granulomas in the guinea pigs start as aggregations of macrophages and few heterophils, evolving to larger lesions showing central caseous necrosis with mineralisation and abundant acid-fast bacilli, surrounded by a rim of macrophages and lymphocytes in the outer layers of the granuloma. Multinucleated giant cells are very rare and fibrotic capsules are not formed in this animal model.

Aminocoumarin derivatives grafted on graphene oxide - new antimicrobial agents to combat the resistance of Mycobacterium tuberculosis and ESKAPE pathogens

Two hybrid materials, based on 7-amino-4-(trifluoromethyl)coumarin and 7-amino-4-methyl-coumarin that attach covalently to graphene oxide (GO) have been synthesized in two steps: i) increasing the number of carboxyl groups required for functionalization with aminocoumarin derivatives by derivatization of the hydroxyls groups with chloroacetic acid, transforming GO into GO-COOH material; ii) activation of carboxylic groups using the carbodiimide-promoted reaction. The obtained composites were characterized by numerous methods that highlighted their successful obtaining. The antimicrobial activity was evaluated on resistant Mycobacterium tuberculosis strains, as well as on ESKAPE pathogens ((Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) in planktonic and biofilm growth states. The biocompatibility of the materials has been assayed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay as well as by measuring the level of nitric oxide/total reactive oxygen species and superoxide release in treated cells. The results have shown that materials exhibited improved inhibitory activity against resistant M. tuberculosis strains in comparison with GO, but also against planktonic and adherent strains. Also, the tested composites have been proved to be biocompatible on the MRC-5 fibroblast cells, demonstrating their promising potential to develop novel agents effective against multidrug resistant pathogens, including M. tuberculosis, as well as by the activation of a pro-inflammatory and of an oxidative response in the mammalian cells.

Antimycobacterial activity of scopoletin from ethanolic extract of Hymenodictyon floribundum (Hochst. & Steud.) B.L.Rob. Stem bark

The available tuberculosis (TB) therapies are taken for long time with complex regimens associated with adverse effects and drug-drug interactions. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis and HIV co-infections necessitates the need for continued search for new effective anti-TB alternative leads with different mechanisms of action and safety profile. The aim of this study was to isolate and characterize antimycobacterial compounds from Hymenodictyon floribundum (Hochst. & Steud.) B.L.Rob. a plant used traditionally in the management of HIV/AIDS-related conditions. Antimycobacterial activity of the plant extracts and its constituents against Mycobacterium indicus pranii (MIP) and Mycobacterium madagascariense (MM) was tested using a twofold broth micro-dilution technique. Bioassay-guided isolation was used to isolate active compounds. Isolated compounds were also tested for activity against clinical isolates of Mycobacterium tuberculosis (Mtb). The crude plant extract had antimycobacterial activity and its ethyl acetate fraction was the most active with minimum inhibitory concentration (MIC) values of 97 µg/ml and 197 µg/ml against MIP and MM respectively. Three compounds were isolated from the ethyl acetate fraction; 7‑hydroxy-6-methoxycoumarin (1), 7,7′-dihydroxy-6,6′-dimethoxy-3,3′-biscoumarin (2) and 7,7′-dihydroxy-6,6′-dimethoxy-8,8′-biscoumarin (3). Compound 1 had growth inhibitory activity against MIP, MM and Mtb with MIC values of 0.2 M against MIP, 0.41 M against MM, 0.78 M against Mtb1 and 1.63 M against Mtb2. In conclusion, 7-Hydroxy-6- methoxycoumarin exhibited moderate antimycobaterial activity. The findings from this study support the use of H. floribundum by traditional health practitioners for treatment of HIV and AIDS-related conditions.

In-silico transcriptome analysis of antibiotic-treated Mycobacterium tuberculosis identifies novel antibiotic resistance factors

The emergence of drug resistant Mycobacterium tuberculosis strains increases the burden on the treatment of tuberculosis. In this study, through in-silico transcriptome analysis of drug-treated M. tuberculosis samples, novel drug targets for the treatment of drug resistance in tuberculosis were identified. Gene expression datasets of tuberculosis patients samples treated with different antibiotics (Isoniazid, Rifampicin, Pyrazinamide, Bedaquiline and Linezolid) were considered in this study. DESeq2 was used to identify the differentially regulated genes. Novel genes which were up-regulated during antibiotic treatment were identified which could be antibiotic resistance factors. Further, to understand the resistance mechanism of the novel genes, we performed gene ontology and gene network analysis for the differentially up-regulated genes. Thus, the in-silico transcriptome analysis paves way for a deeper understanding of the antibiotic resistance in M. tuberculosis.

CRISPRi-mediated characterization of novel anti-tuberculosis targets: Mycobacterial peptidoglycan modifications promote beta-lactam resistance and intracellular survival.

The lack of effective therapeutics against emerging multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) prompts the identification of novel anti-tuberculosis targets. The essential nature of the peptidoglycan (PG) layer of the mycobacterial cell wall, which features several distinctive modifications, such as the N-glycolylation of muramic acid and the amidation of D-iso-glutamate, makes it a target of particular interest. To understand their role in susceptibility to beta-lactams and in the modulation of host-pathogen interactions, the genes encoding the enzymes responsible for these PG modifications (namH and murT/gatD, respectively) were silenced in the model organism Mycobacterium smegmatis using CRISPR interference (CRISPRi). Although beta-lactams are not included in TB-therapy, their combination with beta-lactamase inhibitors is a prospective strategy to treat MDR-TB. To uncover synergistic effects between the action of beta-lactams and the depletion of these PG modifications, knockdown mutants were also constructed in strains lacking the major beta-lactamase of M. smegmatis BlaS, PM965 (M. smegmatis ΔblaS1) and PM979 (M. smegmatis ΔblaS1 ΔnamH). The phenotyping assays affirmed the essentiality of the amidation of D-iso-glutamate to the survival of mycobacteria, as opposed to the N-glycolylation of muramic acid. The qRT-PCR assays confirmed the successful repression of the target genes, along with few polar effects and differential knockdown level depending on PAM strength and target site. Both PG modifications were found to contribute to beta-lactam resistance. While the amidation of D-iso-glutamate impacted cefotaxime and isoniazid resistance, the N-glycolylation of muramic acid substantially promoted resistance to the tested beta-lactams. Their simultaneous depletion provoked synergistic reductions in beta-lactam MICs. Moreover, the depletion of these PG modifications promoted a significantly faster bacilli killing by J774 macrophages. Whole-genome sequencing revealed that these PG modifications are highly conserved in a set of 172 clinical strains of Mtb, demonstrating their potential as therapeutic targets against TB. Our results support the development of new therapeutic agents targeting these distinctive mycobacterial PG modifications.

Anti Mtb Medicinal Plants Database (AMMPDB): A curated database of Indian anti-tubercular medicinal plants

The utilization of medicinal plants for their therapeutic properties has long been a key component of Indian culture. Unique medicinal characteristics can be found in the phytochemicals that are extracted from these plants. Globally, tuberculosis (TB) burden and management are challenged due to the emergence of new resistant strains of Mycobacterium tuberculosis (Mtb). This highlights the importance of new drug molecules from diverse sources as well as their innovative management options. In this context, the present study formulated an Anti Mtb medicinal plant database (AMMPDB Ver. 1.1), a manually curated database of native Indian medicinal plants that reported anti-tubercular (anti-TB) activities and their potential therapeutic phytochemicals. This is the first-ever freely accessible digital repository. The current version of the database provides users, with information regarding 118 native Indian anti-tubercular medicinal plants and their 3374 phytochemicals. The database provides the following information: Taxonomical ID, botanical description, vernacular names, conservation status, geographical distribution maps, IC-50 value, phytochemical details which include - name, Compound ID, Synonyms, location in plant part, 2D, 3D structures (as per the availability), and their medicinal uses reported in the literature. The tools section of the database is equipped with sequentially catalogued and hyperlinked open-access tools utilized for computational drug designing. A case study has been incorporated under the contributors section to validate the tools section and the phytochemicals of the database. AMMPDB Ver 1.1 will be serviceable to research in computational drug designing and discovery with effectiveness and ease.Database URL: https://www.ammpdb.com/

Detection of katG and inhA Genes Mutation in Rifampicin-Resistant Mycobacterium Tuberculosis Using Line Probe Assay (LPA) In Kebbi, Nigeria

Elimination of tuberculosis remains a public health menace, due to multidrug resistant strains of Mycobacterium tuberculosis, that are resistant to the first-line anti-tubercular drugs. Consequently, detection of resistant strains depends on early diagnosis. Intervention of molecular techniques is essential to reduce mortality and morbidity rates. This study aimed to detect katG and inhA gene mutations among rifampicin resistant strain of Mycobacterium tuberculosis in Kebbi State. A cross-sectional study was conducted which covered all the five major health zones in Kebbi State. Two hundred and forty (240) acid fast bacilli confirmed sputum samples were recruited and subjected to Gene Xpert testing. Positive sputum samples were later subjected to Line Probe Assay technique. 14 sputum samples were resistant to rifampicin out of the 240 confirmed acid fast bacilli sputum samples while 226 were sensitive to rifampicin. Mutations were found at the frequency of 100% for katG gene (katG/S315T) in all the 14 rifampicin resistant samples (rpoB/S531L) at the different health zones in kebbi state using the line probe assay. The research has also detected inhA gene mutation at a frequency of 100% in all rifampicin resistant samples showing that mutation is associated with multi resistance to isoniazid and rifampicin. This study confirms that resistance due to katG and inhA mutation is a better surrogate of multidrug-resistant tuberculosis among TB patients in Kebbi State compared to the single-marker analysis. Hence, early molecular detection of rifampicin resistant strains will suffice in determining the management of multidrug resistant tuberculosis in Kebbi State.

Anti-Mycobacterial Activity of Medicinal Plant Extracts Used in the Treatment of Tuberculosis by Traditional Medicine Practitioners in Uganda

Tuberculosis (TB) remains a public health challenge and one of the leading causes of death worldwide. TB is preventable and curable. However, treatment of tuberculosis has continued to be difficult as a result of rapid increase of multidrug and extensively drug resistant strains of Mycobacterium tuberculosis. Medicinal plants have for centuries been traditionally used in treatment of tuberculosis and similar ailments. They possess antimicrobial properties which render them a new hope as a source of novel bioactive leads in the development of antimycobacterial agents. In this study, 2 plant species commonly used traditionally in Uganda for treatment of tuberculosis, Zanthoxylum leprieurii and Rubia cordifolia were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis strains; pan sensitive MTB H37Rv, Rifampicin resistant TMC 331 strain and two wild strains (one rifampicin resistant and another one rifampicin susceptible). Antimycobacterial activity of aqueous, ethanolic and methanolic plant extracts was determined using Resazurin Microtiter Assay (REMA). Both plant extracts exhibited significant in vitro antimycobacterial activity against all strains of Mycobacterium tuberculosis. Minimum inhibitory concentrations (MIC) of methanolic crude extracts of both plants ranged from 23.4 μg/mL to 187.5 μg/mL. Comparatively, methanol extracts of both plants possessed superior antimycobacterial activity against all Mycobacterium tuberculosis strains. Our findings indicated that both plants exhibited activity against susceptible and resistant strains of Mycobacterium tuberculosis. While antimycobacterial activity of Z. leprieurii confirms results from previous studies, activity of the extracts of R. cordifolia is reported for the first time in East Africa. Further studies aimed at determining the effects of combination of these plant extracts and standard anti-TB drugs should be carried out.

Bioinformatics Analysis to Uncover the Potential Drug Targets Responsible for Mycobacterium tuberculosis Peptidoglycan and Lysine Biosynthesis.

Drug-resistant tuberculosis (TB), which results mainly from the selection of naturally resistant strains of Mycobacterium tuberculosis (MTB) due to mismanaged treatment, poses a severe challenge to the global control of TB. Therefore, screening novel and unique drug targets against this pathogen is urgently needed. The metabolic pathways of Homo sapiens and MTB were compared using the Kyoto Encyclopedia of Genes and Genomes tool, and further, the proteins that are involved in the metabolic pathways of MTB were subtracted and proceeded to protein-protein interaction network analysis, subcellular localization, drug ability testing, and gene ontology. The study aims to identify enzymes for the unique pathways for further screening to determine the feasibility of the therapeutic targets. The qualitative characteristics of 28 proteins identified as drug target candidates were studied. The results showed that 12 were cytoplasmic, 2 were extracellular, 12 were transmembrane, and 3 were unknown. Furthermore, druggability analysis revealed 14 druggable proteins, of which 12 were novel and responsible for MTB peptidoglycan and lysine biosynthesis. The novel targets obtained in this study are used to develop antimicrobial treatments against pathogenic bacteria. Future studies should further shed light on the clinical implementation to identify antimicrobial therapies against MTB.

An In-Silico Reverse Vaccinology Approach in Predicting Vaccine Candidate Against Mycobacterium tuberculosis CCDC5180

A quarter of the world’s population is thought to be latently infected with Mycobacterium tuberculosis, creating a vast pool of possible future illnesses. Combined with the rising prevalence of multi-drug resistant Mycobacterium tuberculosis (Mtb) strains, TB poses one of the biggest challenges for world health, and the TB epidemic can only be eradicated with a new and more effective vaccine strategy. Since the Bacille Calmette-Guérin (BCG) vaccine is the only one used to treat tuberculosis (TB), Reverse vaccine technology aims to accelerate the development of subunit vaccines by identifying specific proteins in a pathogenic bacterial proteome that may be protective antigens. This approach was employed on four extracellular proteins namely Secreted fibronectin-binding protein C antigen 85-C, PE-PGRS family protein, Invasion protein RipA, and Invasion protein RipB. The shortlisted proteins were subjected to B-cell, CTL, and HTL epitope prediction. To further identify the most promising epitopes, specialized filtering techniques were employed to narrow down CTL epitopes that were non-allergenic, non-toxic, and antigenic as well as B-cell epitopes that produced antibodies. Similarly, HTL epitopes that generate IFN- γ but not IL-10 were selected. The analysis revealed invasion protein RipA as a potential candidate for Mycobacterium tuberculosis CCDC5180 immunization.

Dithiocarbamates and dithiocarbonates containing 6-nitrosaccharin scaffold: Synthesis, antimycobacterial activity and in silico target prediction using ensemble docking-based reverse virtual screening

Tuberculosis is a curable disease that costs the lives of 1.5 million people per year. It continues to pose a threat to global public health owing to the prevalence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains which make its eradication a continuous challenge. To explore novel and effective antimycobacterial agents, a series of dithiocarbamates/dithiocarbonate-nitrosaccharin hybrids were prepared, characterized by spectral analyses, and assessed for their antimycobacterial activity against M.tuberculosis strain H37Rv. Some compounds showed activity with a minimum inhibitory concentration (MIC) of 0.45–6.09 µg/mL. Reverse ensemble docking against nine putative targets with fifteen different crystal structures was conducted to understand the mechanism of action of the most potent compound 6g. The in silico studies suggested enoyl ACP-reductase (InhA) and polyketide synthase 13 (Pks13) as possible targets for compound 6g.

An In-Silico Evaluation of Anthraquinones as Potential Inhibitors of DNA Gyrase B of Mycobacterium tuberculosis.

The World Health Organization reported that tuberculosis remains on the list of the top ten threats to public health worldwide. Among the main causes is the limited effectiveness of treatments due to the emergence of resistant strains of Mycobacterium tuberculosis. One of the main drug targets studied to combat M. tuberculosis is DNA gyrase, the only enzyme responsible for regulating DNA topology in this specie and considered essential in all bacteria. In this context, the present work tested the ability of 2824 anthraquinones retrieved from the PubChem database to act as competitive inhibitors through interaction with the ATP-binding pocket of DNA gyrase B of M. tuberculosis. Virtual screening results based on molecular docking identified 7122772 (N-(2-hydroxyethyl)-9,10-dioxoanthracene-2-sulfonamide) as the best-scored ligand. From this anthraquinone, a new derivative was designed harbouring an aminotriazole moiety, which exhibited higher binding energy calculated by molecular docking scoring and free energy calculation from molecular dynamics simulations. In addition, in these last analyses, this ligand showed to be stable in complex with the enzyme and further predictions indicated a low probability of cytotoxic and off-target effects, as well as an acceptable pharmacokinetic profile. Taken together, the presented results show a new synthetically accessible anthraquinone with promising potential to inhibit the GyrB of M. tuberculosis.

Molecular Docking Interaction of Mycobacterium Tuberculosis Enoyl-Acp-Reductase Enzyme with Delamaind

One of the eldest human diseases is tuberculosis (TB), for which there is molecular evidence dating back more than 17,000 years. Unfortunately, TB is still one of the top 10 infectious diseases that kill people worldwide, second only to HIV, despite advances in detection and treatment. The World Health Organization (WHO) claims that TB is an international pandemic. It is the main cause of death for those with HIV. In India, the fight against TB has largely been divided into three eras throughout its history: the early era, before the development of x-ray and chemotherapy; the post- independence era, when national TB control programmes were started and put into place; and the current era, when an ongoing WHO-assisted TB control programme is in place. Today's DOTS in India. A new anti-tuberculosis (TB) medication called delamanid, a nitroimidazo-oxazole derivative, has strong in-vitro and in- vivo antitubercular action against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. With intention to propose the most probable mechanism of action of delamanid the docking based computational analysis has been performed against enyl ACP reductase (InhA) as targeted protein. The molecular docking of delamanid with enyl ACP reductase (InhA) showed binding energy (Kcal/mol) -10.86 having molecular interaction Lys165, Ala198, Phe149, Pro193, Met199, Glu219, Pro156, Met103 &amp; Gly96. The concluding consequences of the existing research found out that the chosen molecule highly bounded with InhA thereby inhibiting the mycobacterial cell wall synthesis.

Marine Macrolides to Tackle Antimicrobial Resistance of Mycobacterium tuberculosis.

Tuberculosis has become a major health problem globally. This is worsened by the emergence of resistant strains of Mycobacterium tuberculosis showing ability to evade the effectiveness of the current antimycobacterial therapies. Therefore, the efforts carried out to explore new entities from many sources, including marine, are critical. This review summarizes several marine-derived macrolides that show promising activity against M. tuberculosis. We also provide information regarding the biosynthetic processes of marine macrolides, including the challenges that are usually experienced in this process. As most of the studies reporting the antimycobacterial activities of the listed marine macrolides are based on in vitro studies, the future direction should consider expanding the trials to in vivo and clinical trials. In addition, in silico studies should also be explored for a quick screening on marine macrolides with potent activities against mycobacterial infection. To sum up, macrolides derived from marine organisms might become therapeutical options for tackling antimycobacterial resistance of M. tuberculosis.

Whole genome sequencing of Bulgarian rifampicin resistant Mycobacterium tuberculosis strains.

The transmission of drug-resistant tuberculosis is one of the greatest challenges facing the global tuberculosis control. The aim of the study was to investigate the resent transmission of rifampicin resistant tuberculosis in Bulgaria and to describe the mutations related to the antimicrobials' resistance using whole genome sequencing. As part of an ECDC funded pilot study for evaluation of the systematic use of whole genome sequencing (WGS) of Mycobacterium tuberculosis (MTB) surveillance (EUSeqMyTB), Bulgaria provided 65 rifampicin resistant isolates over a three years' timeframe (2017-2019) representing 87.5% of the notified rifampicin resistant cases. Drug resistance prediction and relatedness analysis of the resistant isolates was performed in collaboration with San Raffaele Scientific Institute, Milan, Italy. Almost all of the isolates were identified as Euro-American lineage (96.9%); 18.5% of the isolates were found to be resistant to fluoroquinolones, but no mutations conferring resistance to bedaquiline or linezolid could be identified. Less than half (43.3%) of the isolates were clustered (<5 SNPs distance) into a total of seven national SNP-based clusters, while a total of six isolates were found to be part of different cross-border clusters. All clustered cases originated from Bulgaria. WGS has proven to be a reliable tool for surveillance and tracing of recent transmission of tuberculosis and has the potential for resistance prediction for most of the antituberculosis drugs.

Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis.

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).