Essential Role of MHC II in the Antitubercular Efficacy of Pyrazinamide.

Antibacterial drug mechanisms have traditionally been examined through a drug-pathogen lens, often overlooking the host's role in shaping drug activity. However, growing evidence suggests that the host environment is crucial for antibacterial efficacy. Pyrazinamide (PZA), a key component of modern tuberculosis therapy, exemplifies this complexity-exhibiting potent activity despite its inability to reduce viability in standard culture.

Mechanism of the dual action self-potentiating antitubercular drug morphazinamide.

Pyrazinamide (PZA) is a cornerstone of first-line antitubercular drug therapy and is unique in its ability to kill nongrowing populations of through disruption of coenzyme A (CoA) metabolism. Unlike other drugs, PZA action is conditional and requires potentiation by host-relevant environmental stressors, such as low pH and nutrient limitation. Despite its pivotal role in tuberculosis therapy, the durability of this crucial drug is challenged by the emergent spread of drug resistance.

Identification of as a potential source of antimycobacterial components.

is a medicinal plant from the Solanaceae family, having medicinal properties and some toxic effects. It is widely distributed across Asia, Africa, Europe, the Americas, and other tropical and subtropical regions, where it is utilized by local pharmaceutical industries. In this study, bioassay-guided fractionation and LC-MS/MS analysis were used for the identification of secondary metabolites with anti-tuberculosis activity in methanolic leaf extracts of .

Discovery of antitubercular potential of trans-3-indoleacrylic acid and its derivatives targeting Mycobacterium tuberculosis: A combined in vitro and in silico investigation.

The persistent global health challenges posed by Mycobacterium tuberculosis (Mtb) underscore the urgent need to identify novel antitubercular agents from natural origin. The objective of this research is to assess the antitubercular potential of phytocompounds from Datura innoxia against Mtb through in vitro and in silico methods. Eleven natural compounds were screened for antitubercular activity.

Lead Informed Artificial Intelligence Mining of Antitubercular Host Defense Peptides.

Identifying host defense peptides (HDPs) that are effective against drug-resistant infections is challenging due to their vast sequence space. Artificial intelligence (AI)-guided design can accelerate HDP discovery, but it traditionally requires large data sets to operationalize. We report an AI workflow that utilizes limited data sets (∼100 peptides) to uncover potent, selective, and safe HDPs by informing selection through lead candidate mutational scanning.

A -Translation Inhibitor is Potentiated by Zinc and Kills and Nontuberculous Mycobacteria.

poses a serious challenge for human health, and new antibiotics with novel targets are needed. Here we demonstrate that an acylaminooxadiazole, MBX-4132, specifically inhibits the -translation ribosome rescue pathway to kill . Our data demonstrate that MBX-4132 is bactericidal against multiple pathogenic mycobacterial species and kills in macrophages.

Oxidative stress drives potent bactericidal activity of pyrazinamide against .

Pyrazinamide (PZA) is a critical component of tuberculosis first-line therapy due to its ability to kill both growing and non-replicating drug-tolerant populations of within the host. Recent evidence indicates that PZA acts through disruption of coenzyme A synthesis under conditions that promote cellular stress. In contrast to its bactericidal action , PZA shows weak bacteriostatic activity against in axenic culture.

A -translation inhibitor is potentiated by zinc and kills and non-tuberculous mycobacteria.

poses a serious challenge for human health, and new antibiotics with novel targets are needed. Here we demonstrate that an acylaminooxadiazole, MBX-4132, specifically inhibits the -translation ribosome rescue pathway to kill . Our data demonstrate that MBX-4132 is bactericidal against multiple pathogenic mycobacterial species and kills in macrophages.

A Nucleophilic Activity-Based Probe Enables Profiling of PLP-Dependent Enzymes.

PLP-dependent enzymes represent an important class of highly "druggable" enzymes that perform a wide array of critical reactions to support all organisms. Inhibition of individual members of this family of enzymes has been validated as a therapeutic target for pathologies ranging from infection with Mycobacterium tuberculosis to epilepsy. Given the broad nature of the activities within this family of enzymes, we envisioned a universally acting probe to characterize existing and putative members of the family that also includes the necessary chemical moieties to enable activity-based protein profiling experiments.

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M.

Discovery and Optimization of 6-(1-Substituted pyrrole-2-yl)--triazine Containing Compounds as Antibacterial Agents.

Antimicrobial drug resistance is a major health issue plaguing healthcare worldwide and leading to hundreds of thousands of deaths globally each year. Tackling this problem requires discovery and development of new antibacterial agents. In this study, we discovered novel 6-(1-substituted pyrrole-2-yl)--triazine containing compounds that potently inhibited the growth of regardless of its methicillin-resistant status, displaying minimum inhibitory concentration (MIC) values as low as 1 μM.

Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).

Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells.

Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis.

Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined.

Structure-Aware Mycobacterium tuberculosis Functional Annotation Uncloaks Resistance, Metabolic, and Virulence Genes.

Accurate and timely functional genome annotation is essential for translating basic pathogen research into clinically impactful advances. Here, through literature curation and structure-function inference, we systematically update the functional genome annotation of Mycobacterium tuberculosis virulent type strain H37Rv. First, we systematically curated annotations for 589 genes from 662 publications, including 282 gene products absent from leading databases.

Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry.

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue.

Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing - Implication for metabolic remodeling.

The global incidence of the human nontuberculous mycobacteria (NTM) disease is rapidly increasing. However, knowledge of gene essentiality under optimal growth conditions and conditions relevant to the natural ecology of NTM, such as hypoxia, is lacking. In this study, we utilized transposon sequencing to comprehensively identify genes essential for growth in Mycobacterium intracellulare.

The Bewildering Antitubercular Action of Pyrazinamide.

Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear.

Impact of the host environment on the antitubercular action of pyrazinamide.

Pyrazinamide remains the only drug in the tuberculosis pharmacopeia to drastically shorten first-line therapy from nine to six months. Due to its unparalleled ability to sterilize non-replicating bacilli and reduce relapse rates, PZA is expected to be irreplaceable in future therapies against tuberculosis. While the molecular target of PZA is unclear, recent pharmacokinetic studies using small animal models and patient samples have highlighted the importance of host metabolism and immune responses in PZA efficacy.

Revitalizing antifolates through understanding mechanisms that govern susceptibility and resistance.

In prokaryotes and eukaryotes, folate (vitamin B) is an essential metabolic cofactor required for all actively growing cells. Specifically, folate serves as a one-carbon carrier in the synthesis of amino acids (such as methionine, serine, and glycine), -formylmethionyl-tRNA, coenzyme A, purines and thymidine. Many microbes are unable to acquire folates from their environment and rely on folate biosynthesis.

Genomewide Assessment of Mycobacterium tuberculosis Conditionally Essential Metabolic Pathways.

A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in , the major causative agent of tuberculosis, using a combination of transposon insertion sequencing (Tn-seq) and comparative genomic analysis. To identify conditionally essential genes by Tn-seq, we used media with different nutrient compositions.

Methionine Antagonizes -Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in .

-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, -aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs.

Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is a widely used synergistic antimicrobial combination to treat a variety of bacterial and certain fungal infections. These drugs act by targeting sequential steps in the biosynthetic pathway for tetrahydrofolate (THF), where SMX inhibits production of the THF precursor dihydropteroate, and TMP inhibits conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production and this mono-potentiation mechanism is the current explanation for their synergistic action.