Functionalized regioisomers of the natural product phenazines myxin and iodinin as potent inhibitors of Mycobacterium tuberculosis and human acute myeloid leukemia cells.

The natural bioactive products myxin and iodinin are phenazine 5,10-dioxides possessing potent anti-bacterial and anti-cancer activity in vitro. This work describes the synthesis and derivatization of new myxin and iodinin regioisomers, developed from 1,3-dihydroxyphenazine 5,10-dioxide. Compounds were evaluated for activity towards M.

Antimicrobial and Antibiofilm Effects of Bithionol against .

() is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 μM against type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against were identified.

Activity against of a new class of spirooxindolopyrrolidine embedded chromanone hybrid heterocycles.

A new class of structurally intriguing heterocycles embedded with spiropyrrolidine, oxindole and chromanones was prepared by regio- and stereoselectively in quantitative yields using an intermolecular tandem cycloaddition protocol. The compounds synthesized were assayed for their anti-mycobacterial activity against () H37Rv and isoniazid-resistant ( and promoter mutations) clinical isolates. Four compounds exhibited significant antimycobacterial activity against strains tested.

Identification of essential oils with strong activity against stationary phase .

Purpose: To identify essential oils (EOs) active against non-growing stationary phase and multidrug-resistant strains.

Methods: The activity of EOs against both stationary and log phase was evaluated by colony forming unit (CFU) assay and minimum inhibitory concentration (MIC) testing.

Results: We assessed the activity of 80 EOs against stationary phase and found 12 EOs (Cinnamon, Satureja montana, Palmarosa, Lemon eucalyptus, Honey myrtle, Combava, Health shield, Mandarin, Thyme, Rosewood, Valerian Root and Basil) at 0.

Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.

Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme.

Novel Quinoline-Based Thiosemicarbazide Derivatives: Synthesis, DFT Calculations, and Investigation of Antitubercular, Antibacterial, and Antifungal Activities.

The discovery of new antimicrobial agents as a means of treating drug-resistant microbial pathogens is of utmost significance to overcome their immense risk to human well-being. The current investigation involves the development, synthesis, and assessment of the antimicrobial efficacy of novel quinoline derivatives incorporating a thiosemicarbazide functionality. To design the target compounds (-), we applied the molecular hybridization approach to link various thiosemicarbazides to the quinoline core with a sulfonyl group.

Design, Synthesis, and Evaluation of Novel Δ-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mutant.

() drug resistance poses an alarming threat to global tuberculosis control. We previously reported that , a ring-fused thiazolo-2-pyridone, inhibits respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant isolates. This discovery revealed a new strategy to address INH resistance.

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity.

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of (). In the present study, we aimed to chemically tailor INH to overcome this resistance.

Urea derivatives carrying a thiophenylthiazole moiety: Design, synthesis, and evaluation of antitubercular and InhA inhibitory activities.

The recent emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) has complicated and significantly slowed efforts to eradicate and/or reduce the worldwide incidence of life-threatening acute and chronic cases of tuberculosis. To overcome this setback, researchers have increased the intensity of their work to identify new small-molecule compounds that are expected to remain efficacious antimicrobials against Mtb. Here, we describe our effort to apply the principles of molecular hybridization to synthesize 16 compounds carrying thiophene and thiazole rings beside the core urea functionality (TTU1-TTU16).

Proteome Profiling of Cells Exposed to Nitrosative Stress.

Reactive nitrogen species (RNS) are secreted by human cells in response to infection by (Mtb). Although RNS can kill Mtb under some circumstances, Mtb can adapt and survive in the presence of RNS by a process that involves modulation of gene expression. Previous studies focused primarily on stress-related changes in the Mtb transcriptome.

Whole Genome Sequencing of Drug Resistant and Drug Susceptible Isolates From Tigray Region, Ethiopia.

Tuberculosis, mainly caused by Mycobacterium tuberculosis (Mtb), is an ancient human disease that gravely affects millions of people annually. We wanted to explore the genetic diversity and lineage-specific association of Mtb with drug resistance among pulmonary tuberculosis patients. Sputum samples were collected from pulmonary tuberculosis patients at six different healthcare institutions in Tigray, Ethiopia, between July 2018 and August 2019.

Serum proteases prevent bacterial biofilm formation: role of kallikrein and plasmin.

Biofilm formation is a general strategy for bacterial pathogens to withstand host defense mechanisms. In this study, we found that serum proteases inhibit biofilm formation by , and . Confocal laser-scanning microscopy analysis revealed that these proteins reduce the biomass and alter the architecture of meningococcal biofilms.

Correction: Characteristics of pulmonary multidrug-resistant tuberculosis patients in Tigray Region, Ethiopia: A cross-sectional study.

[This corrects the article DOI: 10.1371/journal.pone.

Lipid droplets and the transcriptome of Mycobacterium tuberculosis from direct sputa: a literature review.

Mycobacterium tuberculosis (Mtb), the main etiology of tuberculosis (TB), is predominantly an intracellular pathogen that has caused infection, disease and death in humans for centuries. Lipid droplets (LDs) are dynamic intracellular organelles that are found across the evolutionary tree of life. This review is an evaluation of the current state of knowledge regarding Mtb-LD formation and associated Mtb transcriptome directly from sputa.

Frequency and patterns of first- and second-line drug resistance-conferring mutations in Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in a cross-sectional study in Tigray Region, Ethiopia.

Objectives: Tuberculosis (TB) is a preventable and treatable infectious disease, but the continuing emergence and spread of multidrug-resistant TB is threatening global TB control efforts. This study aimed to describe the frequency and patterns of drug resistance-conferring mutations of Mycobacterium tuberculosis (MTB) isolates detected from pulmonary TB patients in Tigray Region, Ethiopia.

Methods: A cross-sectional study design was employed to collect sputum samples from pulmonary TB patients between July 2018 to August 2019.

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease.

Alzheimer disease (AD) is a devastating neurological disease associated with progressive loss of mental skills and cognitive and physical functions whose etiology is not completely understood. Here, our goal was to simultaneously uncover novel and known molecular targets in the structured layers of the hippocampus and olfactory bulbs that may contribute to early hippocampal synaptic deficits and olfactory dysfunction in AD mice. Spatially resolved transcriptomics was used to identify high-confidence genes that were differentially regulated in AD mice relative to controls.

Lineage-Specific Proteomic Signatures in the Complex Reveal Differential Abundance of Proteins Involved in Virulence, DNA Repair, CRISPR-Cas, Bioenergetics and Lipid Metabolism.

Despite the discovery of the tubercle bacillus more than 130 years ago, its physiology and the mechanisms of virulence are still not fully understood. A comprehensive analysis of the proteomes of members of the human-adapted complex (MTBC) lineages 3, 4, 5, and 7 was conducted to better understand the evolution of virulence and other physiological characteristics. Unique and shared proteomic signatures in these modern, pre-modern and ancient MTBC lineages, as deduced from quantitative bioinformatics analyses of high-resolution mass spectrometry data, were delineated.

Characteristics of pulmonary multidrug-resistant tuberculosis patients in Tigray Region, Ethiopia: A cross-sectional study.

Background: Tuberculosis (TB) is among the top 10 causes of mortality and the first killer among infectious diseases worldwide. One of the factors fuelling the TB epidemic is the global rise of multidrug resistant TB (MDR-TB). The aim of this study was to determine the magnitude and factors associated with MDR-TB in the Tigray Region, Ethiopia.

Antibiotic resistance: turning evolutionary principles into clinical reality.

Antibiotic resistance is one of the major challenges facing modern medicine worldwide. The past few decades have witnessed rapid progress in our understanding of the multiple factors that affect the emergence and spread of antibiotic resistance at the population level and the level of the individual patient. However, the process of translating this progress into health policy and clinical practice has been slow.

Molecular epidemiology of M. tuberculosis in Ethiopia: A systematic review and meta-analysis.

The molecular epidemiology of Mycobacterium tuberculosis (M. tuberculosis, Mtb) is poorly documented in Ethiopia. The data that exists has not yet been collected in an overview metadata form.

Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide.

Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.

Ample glycosylation in membrane and cell envelope proteins may explain the phenotypic diversity and virulence in the Mycobacterium tuberculosis complex.

Multiple regulatory mechanisms including post-translational modifications (PTMs) confer complexity to the simpler genomes and proteomes of Mycobacterium tuberculosis (Mtb). PTMs such as glycosylation play a significant role in Mtb adaptive processes. The glycoproteomic patterns of clinical isolates of the Mycobacterium tuberculosis complex (MTBC) representing the lineages 3, 4, 5 and 7 were characterized by mass spectrometry.