A5043334368- Antibiotic Resistance in Bacteria
- Antimicrobial Resistance in Staphylococcus
- Click Chemistry and Applications
- Biochemical and Molecular Research
- Antibiotics Pharmacokinetics and Efficacy
- Pneumocystis jirovecii pneumonia detection and treatment
- Tuberculosis Research and Epidemiology
- Antimicrobial agents and applications
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Pneumonia and Respiratory Infections
- Synthesis and biological activity
- Microbial Metabolism and Applications
- Cancer therapeutics and mechanisms
- Microbial Natural Products and Biosynthesis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Enzyme Structure and Function
- Advanced Fluorescence Microscopy Techniques
- HIV/AIDS drug development and treatment
- Antibiotic Use and Resistance
- Infant Nutrition and Health
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Biopolymer Synthesis and Applications
St. Jude Children's Research Hospital
2019-2024
University of Connecticut
2014-2022
Texas Tech University Health Sciences Center
2020
Texas Tech University
2020
University of Montana
2019
Pfizer (United States)
2019
Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics diagnostics. It is thereby key to a comprehensive genome-wide understanding of process antibiotic stress, modulation the involved processes affects their ability overcome said stress. Here we undertake genetic analysis human pathogen Streptococcus pneumoniae responds 20 antibiotics. We build atlas drug susceptibility determinants generated interaction network that...
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...
Significance Computationally predicting drug resistance mutations early in the discovery phase would be an important breakthrough development. The most meaningful predictions of target will show reduced affinity for while maintaining viability complex context a cell. Here, protein design algorithm K* Osprey was used to predict single-nucleotide polymorphism dihydrofolate reductase that confers experimental antifolate preclinical phase. Excitingly, mutation also selected bacteria under...
While antifolates such as Bactrim (trimethoprim-sulfamethoxazole; TMP-SMX) continue to play an important role in treating community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), resistance-conferring mutations, specifically F98Y of dihydrofolate reductase (DHFR), have arisen and compromise continued use. In attempt extend the lifetime this class, we developed a class propargyl-linked (PLAs) that exhibit potent inhibition enzyme bacterial strains. Probing configuration at...
Although classical, negatively charged antifolates such as methotrexate possess high affinity for the dihydrofolate reductase (DHFR) enzyme, they are unable to penetrate bacterial cell wall, rendering them poor antibacterial agents. Herein, we report a new class of propargyl-linked that capture some key contacts common classical while maintaining ability passively diffuse across wall. Eight synthesized compounds exhibit extraordinary potency against Gram-positive S. aureus with limited...
Drug-resistant enzymes must balance catalytic function with inhibitor destabilization to provide a fitness advantage. This sensitive balance, often involving very subtle structural changes, be achieved through selection process minimal number of eligible point mutations. As part program design propargyl-linked antifolates (PLAs) against trimethoprim-resistant dihydrofolate reductase (DHFR) from Staphylococcus aureus, we have conducted thorough study several clinically observed chromosomal...
Mycobacterium tuberculosis continues to cause widespread, life-threatening disease. In the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (MDR XDR) bacteria have spread globally number of agents that effectively treat these infections is significantly reduced. We been developing propargyl-linked antifolates (PLAs) potent inhibitors essential enzyme dihydrofolate reductase (DHFR) from recently found charged PLAs with partial zwitterionic character...
The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors dihydrofolate reductase (DHFR), ineffective. Continued exploitation these targets will require compounds that can broadly inhibit resistance-conferring isoforms. Using a structure-based approach, we have developed novel class ionized nonclassical antifolates (INCAs) capture the molecular interactions been exclusive to classical antifolates. These...
Increasing rates of drug-resistant Gram-negative (GN) infections, combined with a lack new GN-effective antibiotic classes, are driving the need for discovery agents. Bacterial metabolism represents an underutilized mechanism action in current antimicrobial therapies. Therefore, we sought to identify novel antimetabolites that disrupt key metabolic pathways and explore specific impacts these agents on bacterial metabolism. This study describes successful application this approach discover...
Poor penetration through the outer membrane (OM) of Gram-negative bacteria is a major barrier antibiotic development. While β-lactam antibiotics are commonly used against
We discovered azaindole-based compounds with weak innate activity that exhibit substantial potentiation of antibacterial activities different antibiotics, viz., rifampicin, erythromycin, solithromycin, and novobiocin in Gram-negative bacteria. In the presence azaindole derivatives, these antibiotics exhibited submicromolar minimum inhibitory concentrations (MICs) against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii. The fold improvements MIC were...
Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this variant, yet substitution still reduces efficacy of these agents. Surprisingly, differences enantiomeric configuration at stereogenic center PLAs influence isomeric...
Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, effects deoxygenation 2- and positions on spectinomycin actinamine ring are probed evaluate their relationship ribosomal binding antimicrobial activities spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), spectinamides. To generate these analogs, improved synthesis...
Multidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed adoption of new technologies. It is imperative that we create mechanistic insights based on latest technologies, use translational strategies to optimize patient therapy. Although drug relied minimal inhibitory concentration testing established vitro mouse infection models, limited...
Infections due to Gram-negative bacteria are increasingly dangerous the spread of multi-drug resistant strains, emphasizing urgent need for new antibiotics with alternative modes action. We have previously identified a novel class antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode action which is dependent on activation by cysteine synthase A. Herein, we report detailed examination anti-E. coli structure-activity relationship...
Pharmacokinetic/pharmacodynamic properties are strongly correlated with the in vivo efficacy of antibiotics. Propargyl-linked antifolates, a novel class antibiotics, demonstrate potent antibacterial activity against both Gram-positive and Gram-negative pathogenic bacteria, including multidrug-resistant <i>Staphylococcus aureus</i>. Here, we report our efforts to optimize pharmacokinetic profile this best match established pharmacodynamic properties. High-resolution crystal structures were...