A5102896624- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Antibiotic Resistance in Bacteria
- Protein Degradation and Inhibitors
- Antibiotics Pharmacokinetics and Efficacy
- Calpain Protease Function and Regulation
- PI3K/AKT/mTOR signaling in cancer
- Inhalation and Respiratory Drug Delivery
- Antimicrobial Resistance in Staphylococcus
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Signaling Pathways in Disease
- RNA and protein synthesis mechanisms
- Antifungal resistance and susceptibility
- Antimicrobial Peptides and Activities
- Venomous Animal Envenomation and Studies
- Fungal and yeast genetics research
- Obstructive Sleep Apnea Research
- Bioactive Compounds and Antitumor Agents
- Tracheal and airway disorders
- Sulfur-Based Synthesis Techniques
St. Jude Children's Research Hospital
2015-2024
Colorado State University
2024
RTI International
2024
University of Tennessee Health Science Center
2006-2024
Shenyang Pharmaceutical University
2021-2024
Second Hospital of Anhui Medical University
2021
Anhui Medical University
2021
Memphis Health Center
2015
The Ohio State University
2006
Mycobacterium abscessus ( Mab ), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified distinct structural subclass N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up 64-fold more potent against over parent SPC. Mechanism...
Abstract Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis not traditionally used in treatment potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using laboratory strain H37Rv, lead spectinamide 1599 and a broad panel 27 antibiotics. In vitro ,...
Trehalose is a disaccharide essential for the survival and virulence of pathogenic fungi. The biosynthesis trehalose requires trehalose-6-phosphate synthase, Tps1, phosphatase, Tps2. Here, we report structures N-terminal domain Tps2 (Tps2NTD) from Candida albicans, transition-state complex C-terminal phosphatase (Tps2PD) bound to BeF3 trehalose, catalytically dead Tps2PD(D24N) Cryptococcus neoformans (T6P). Tps2NTD closely resembles structure Tps1 but lacks any catalytic activity....
Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their activity is derived from both ribosomal affinity and their ability overcome intrinsic efflux mediated by Mycobacterium Rv1258c pump. This study explores structure-activity relationships through analysis 50 targeted spectinamides. Compounds evaluated for translational inhibition, MIC in pump deficient wild type strains, efficacy an acute model infection. The...
Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment tuberculosis (TB) in humans. The spectinamides narrow-spectrum semisynthetic analogues spectinomycin, modified avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead 1599, have been previously shown exhibit a promising therapeutic profile mice as single agents. Here we explore the vivo activity when combined with other Methods:...
Infections caused by fungal pathogens such as Candida and Cryptococcus are associated with high mortality rates, partly due to limitations in the current antifungal arsenal. This highlights need for drug targets novel mechanisms of action. The trehalose biosynthesis pathway is a promising target because essential virulence neoformans albicans also mediator stress responses, thermotolerance. To exploit its untapped potentials, we screened St. Jude 3-point pharmacophore library identify small...
The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes first step biosynthesis fungi. Here, we report structures eukaryotic Tps1s complex with substrates or substrate analogues. overall Tps1 from Candida albicans and Aspergillus fumigatus are essentially identical reveal N- C-terminal Rossmann fold domains that form glucose-6-phosphate UDP-glucose binding sites, respectively. These analogues key residues...
Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation the bacterial caseinolytic protease (ClpP). The ability ClpP activators to kill nongrowing bacteria represents new opportunity combat deep-seated biofilm infections. However, acyldepsipeptide scaffold is subject rapid metabolism. Herein, we explore alteration potentially metabolically reactive α,β unsaturated acyl chain. Through targeted synthesis, phenyl urea substituted depsipeptide with...
The lengthy treatment time for tuberculosis (TB) is a primary cause the emergence of multidrug resistant (MDR-TB). One approach to improve TB therapy develop an inhalational that when administered in combination with oral drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues spectinomycin excellent activity against Mycobacterium (Mtb), including MDR XDR Mtb strains. Spectinamide-1599 was chosen as promising candidate development therapy. Using murine model...
The pregnane X receptor (PXR) regulates the metabolism and excretion of xenobiotics endobiotics by regulating expression drug-metabolizing enzymes transporters. unique structure PXR allows it to bind many drugs drug leads, possibly causing undesired drug-drug interactions. Therefore, is crucial evaluate whether chemicals or PXR. Fluorescence-based assays are preferred because their sensitivity nonradioactive nature. On basis our previously characterized 4 (BODIPY FL vinblastine), a...
Despite decades of research, tuberculosis remains a leading cause death from single infectious agent. Spectinamides are promising novel class antituberculosis agents, and the lead spectinamide 1810 has demonstrated excellent efficacy, safety, drug-like properties in numerous vitro vivo assessments mouse models tuberculosis. In current dose ranging fractionation study, we used 29 different combinations level dosing frequency to characterize exposure-response relationship for model...
The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This achieved remarkable results as almost 90% multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). AEs associated with long-term administration protein synthesis inhibitor linezolid. Spectinamide 1599 is...
A new series of spectinomycin analogs with potency against drug-resistant bacterial pathogens was designed and developed a structure-based approach validated in vitro vivo.
Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs that abolish mycolic acid biosynthesis kill Mycobacterium tuberculosis (Mtb) through the inhibition of essential type II fatty synthase (FAS-II) dehydratase HadAB. While mutations preventing ISO TAC either from being converted to their active form or covalently modifying target most frequent spontaneous associated with high-level resistance both drugs, molecular mechanisms underlying Mtb strains harboring missense in second,...
Ligands for cereblon, a component of functional E3 ligase complex that targets proteins proteolysis, are critical developing molecular glues and proteolysis-targeting chimeras (PROTACs), which have therapeutic implications various diseases. However, the lack sensitivity previously reported assays limits characterization cereblon ligands. To address this shortcoming, we developed BODIPY FL thalidomide (10) as high-affinity fluorescent probe human protein, with Kd value 3.6 nM. We then used to...
The successful treatment of Helicobacter pylori infections is becoming increasingly difficult due to the rise resistance against current broad spectrum triple therapy regimens. In search for narrow-spectrum agents H. pylori, a high-throughput screen identified two structurally related thienopyrimidine compounds that selectively inhibited over commensal members gut microbiota. To develop structure–activity relationship (SAR) thienopyrimidines this study employed four series modifications in...
Spectinamides are promising new semisynthetic anti-tubercular agents that modified with a pyridyl side chain, which blocks native efflux from the tuberculosis cell. This study, describes stability of an advanced panel spectinamide analogs, varying substitutions to Phase-II conjugative metabolism by glucuronosyl transferase, sulfotransferase and glutathione-S-transferase enzymes using both human rat S9 enzyme fractions. All solely 5-substituted spectinamides exhibited complete towards Phase...