Developing novel indoles as antitubercular agents and simulated annealing-based analysis of their binding with MmpL3.

Aim: This research aimed to develop novel indole-2-carboxamides as potential antitubercular agents using rational drug design. It also focused on identifying the critical interactions required for these compounds to exhibit effective antitubercular activity.

Materials And Methods: Novel indole-2-carboxamides targeting MmpL3 were designed based on SAR, synthesized, and tested for their antitubercular and induction properties.

Inhibition of DXR in the MEP pathway with lipophilic -alkoxyaryl FR900098 analogs.

In () and (), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. This pathway and its products are vital to bacterial/parasitic metabolism and survival, and represent an attractive set of drug targets due to their essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR).

The Antitubercular Activities of Natural Products with Fused-Nitrogen-Containing Heterocycles.

Tuberculosis (TB) is notorious as the leading cause of death worldwide due to a single infectious entity and its causative agent, (), has been able to evolve resistance to all existing drugs in the treatment arsenal complicating disease management programs. In drug discovery efforts, natural products are important starting points in generating novel scaffolds that have evolved to specifically bind to vulnerable targets not only in pathogens such as , but also in mammalian targets associated with human diseases. Structural diversity is one of the most attractive features of natural products.

MEPicides: α,β-unsaturated Fosmidomycin -Acyl Analogs as Efficient Inhibitors of 1-Deoxy-d-xylulose-5-phosphate reductoisomerase.

Malaria, a mosquito-borne disease caused by several parasites of the genus, remains a huge threat to global public health. There are an estimated 0.5 million malaria deaths each year, mostly among African children.

Molecular insights into Mmpl3 leads to the development of novel indole-2-carboxamides as antitubercular agents.

Tuberculosis (TB) is an air-borne infectious disease and is the leading cause of death among all infectious diseases globally. The current treatment regimen for TB is overtly long and patient non-compliance often leads to drug resistant TB resulting in a need to develop new drugs that will act via novel mechanisms. In this research work, we selected membrane protein large (MmpL3) as the drug target and indole-2-carboximide as our molecule of interest for further designing new molecules.

GSK2556286 Is a Novel Antitubercular Drug Candidate Effective with the Potential To Shorten Tuberculosis Treatment.

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs.

Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones.

Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed cidality as well as intracellular activity against M.

Identification of β-Lactams Active against by a Consortium of Pharmaceutical Companies and Academic Institutions.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill (Mtb).

Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors.

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors.

The Tuberculosis Drug Accelerator at year 10: what have we learned?

The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in TB drug discovery by breaking down barriers among competing labs and institutions, has reached the 10-year landmark. We review the consortium’s achievements, advantages and limitations and advocate for application of similar models to other diseases.

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets.

More than two decades have elapsed since the publication of the first genome sequence of () which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum.

Development and Optimization of Chromosomally-Integrated Fluorescent Reporter Constructs.

resides in the lungs in various lesion types with unique microenvironmental conditions. This diversity is in line with heterogeneous disease progression and divergent drug efficiency. Fluorescent reporter strains can be used to decipher the micromilieu and to guide future treatment regimens.

Tissue specific diversification, virulence and immune response to BCG in a patient with an IFN-γ R1 deficiency.

: We characterized BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. : We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine).

Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among -benzylidene-'-thiazol-2-yl-hydrazines.

Effective treatment of tuberculosis is challenged by the rapid development of () multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor.

Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development.

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice.

Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents.

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M.

C4-Phenylthio β-lactams: Effect of the chirality of the β-lactam ring on antimicrobial activity.

C4-phenylthio β-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria - Mycobacterium tuberculosis (Mtb) and Moraxella catarrhalis (M. cat). These compounds are effective against β-lactamase producing Mtb and M.

Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis.

Mechanisms of magnesium homeostasis in are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg/Co transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg ions conferred resistance to this scaffold.

Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C.

MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria.

Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans.

The present state of the tuberculosis drug development pipeline.

Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates for drug-sensitive disease but requires a 6-month duration of chemotherapy. Drug-resistant disease requires significantly longer treatment durations with drugs associated with a higher risk of adverse events.

Construction of Fluorescent Analogs to Follow the Uptake and Distribution of Cobalamin (Vitamin B) in Bacteria, Worms, and Plants.

Vitamin B is made by only certain prokaryotes yet is required by a number of eukaryotes such as mammals, fish, birds, worms, and Protista, including algae. There is still much to learn about how this nutrient is trafficked across the domains of life. Herein, we describe ways to make a number of different corrin analogs with fluorescent groups attached to the main tetrapyrrole-derived ring.