Development of a luciferase-based Gram-positive bacterial reporter system for the characterization of antimicrobial agents.

Unlabelled: Mechanistic investigations are of paramount importance in elucidating the modes of action of antibiotics and facilitating the discovery of novel drugs. We reported a luciferase-based reporter system using bacterial cells to unveil mechanisms of antimicrobials targeting transcription and translation. The reporter gene encoding NanoLuciferase (NanoLuc) was integrated into the genome of the Gram-positive model organism, , to generate a reporter strain BS2019.

Sulfonamidyl derivatives of sigmacidin: Protein-protein interaction inhibitors targeting bacterial RNA polymerase and sigma factor interaction exhibiting antimicrobial activity against antibiotic-resistant bacteria.

RNA polymerase is an essential enzyme involved in bacterial transcription, playing a crucial role in RNA synthesis. However, it requires the association with sigma factors to initiate this process. In our previous work, we utilized a structure-based drug discovery approach to create benzoyl and benzyl benzoic acid compounds.

Synthesis and antimicrobial activity of an SO-releasing siderophore conjugate.

A novel Trojan Horse conjugate consisting of an SO-releasing 2,4-dinitrobenzenesulfonamide group attached to the monocatecholate siderophore aminochelin was synthesized to examine whether a bidentate catecholate siderophore unit could help potentiate the antimicrobial activity of SO-releasing prodrugs. The conjugate obtained displays rapid SO release on reaction with glutathione, and proved more active against Staphylococcus aureus than a comparable SO-releasing prodrug lacking the siderophore unit, although activity required micromolar concentrations. The conjugate was inactive against wild-type Escherichia coli, but activity was observed against an entA mutant strain that is unable to produce its major siderophores.

Synthesis and biological evaluation of nusbiarylin derivatives as bacterial rRNA synthesis inhibitor with potent antimicrobial activity against MRSA and VRSA.

Bacterial transcription is a valid but underutilized target for antimicrobial agent discovery because of its function of bacterial RNA synthesis. Bacterial transcription factors NusB and NusE form a transcription complex with RNA polymerase for bacterial ribosomal RNA synthesis. We previously identified a series of diarylimine and -amine inhibitors capable of inhibiting the interaction between NusB and NusE and exhibiting good antimicrobial activity.

Multi-methodological approach for the Quality assessment of Senecionis scandentis Herba (Qianliguang) in the herbal market.

We set forth to assess the quality of an herbal medicine sold in Hong Kong called Qianliguang by employing a multi-methodological approach. The quality is set by its identity, chemical composition, and bioactivities, among others. Qianliguang (Senecionis scandentis Herba, Senecio scandens Buch.

Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction.

Transcription is an essential biological process in bacteria requiring a core enzyme, RNA polymerase (RNAP). Bacterial RNAP is catalytically active but requires sigma (σ) factors for transcription of natural DNA templates. σ factor binds to RNAP to form a holoenzyme which specifically recognizes a promoter, melts the DNA duplex, and commences RNA synthesis.

Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen .

The emergence of multidrug resistance in the clinically significant pathogen is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors "nusbiarylins" presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant (MRSA) and the type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations.

Discovery of Antibacterials That Inhibit Bacterial RNA Polymerase Interactions with Sigma Factors.

Formation of a bacterial RNA polymerase (RNAP) holoenzyme by a catalytic core RNAP and a sigma (σ) initiation factor is essential for bacterial viability. As the primary binding site for the housekeeping σ factors, the RNAP clamp helix domain represents an attractive target for novel antimicrobial agent discovery. Previously, we designed a pharmacophore model based on the essential amino acids of the clamp helix, such as R278, R281, and I291 ( numbering), and identified hit compounds with antimicrobial activity that interfered with the core-σ interactions.

First-In-Class Inhibitors Targeting the Interaction between Bacterial RNA Polymerase and Sigma Initiation Factor Affect the Viability and Toxin Release of .

Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound () was previously identified from a pharmacophore model-based screen.

Induction of the long noncoding RNA NBR2 from the bidirectional BRCA1 promoter under hypoxic conditions.

BRCA1 plays an important role in preventing breast cancer and is often silenced or repressed in sporadic cancer. The BRCA1 promoter is bidirectional: it drives transcription of the long non-coding (lnc) NBR2 transcript in the opposite orientation relative to the BRCA1 transcript. Hypoxic conditions repress BRCA1 transcription, but their effect on expression of the NBR2 transcript has not been reported.

PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma.

Protein Tyrosine Phosphatase, Receptor Type G (PTPRG) was identified as a candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). PTPRG induces significant in vivo tumor suppression in NPC. We identified EGFR as a PTPRG potential interacting partner and examined this interaction.

Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter.

Disruption of the BRCA1 tumor suppressor can be caused not only by inherited mutations in familial cancers but also by BRCA1 gene silencing in sporadic cancers. Hypoxia, a key feature of the tumor microenvironment, has been shown to downregulate BRCA1 at the transcriptional level via repressive E2F4/p130 complexes. Here we showed that hypoxia also drives epigenetic modification of the BRCA1 promoter, with decreased H3K4 methylation as a key repressive modification produced by the lysine-specific histone demethylase LSD1.

Aberrant epigenetic silencing is triggered by a transient reduction in gene expression.

Background: Aberrant epigenetic silencing plays a major role in cancer formation by inactivating tumor suppressor genes. While the endpoints of aberrant silencing are known, i.e.