Research News
Clemons Lab
Structures of Bacterial and Human Phosphoglycosyltransferases Bound to a Common Inhibitor Inform Selective Therapeutics
Researchers in the Clemons lab, in collaboration with the Kurosu lab at the University of Tennessee Health Sciences Center, have taken an important step toward designing more precise antibiotics and anticancer drugs by studying two related enzymes found in bacteria and humans. Using cryo‑electron microscopy, they determined how both enzymes, MraY (in bacteria) and DPAGT1 (in humans), bind to the same promising drug molecule, revealing subtle but important differences in how the compound fits into each target. These differences highlight ways to modify the drug so it selectively targets one enzyme over the other, potentially enabling treatments that kill bacteria or cancer cells while minimizing side effects. The work provides a blueprint for designing next‑generation therapeutics by directly comparing how similar proteins interact with the same inhibitor.
Datta Lab
A Nutrient Bottleneck Controls Antibiotic Efficacy in Structured Bacterial Populations
Antibiotic resistance is a growing global health threat. Although antibiotic activity is well studied in homogeneous liquid cultures, many infections are caused by spatially structured multicellular populations where consumption of scarce nutrients establishes strong spatial variations in their abundance. These nutrient variations have long been hypothesized to help bacterial populations tolerate antibiotics, since liquid culture studies link antibiotic tolerance to metabolic activity, and thus, local nutrient availability. Here, we test this hypothesis by visualizing cell death in structured Escherichia coli populations exposed to select nutrients and antibiotics. We find that nutrient availability acts as a bottleneck to antibiotic killing, causing death to propagate through the population as a traveling front. By integrating our measurements with biophysical theory and simulations, we establish quantitative principles that explain how collective nutrient consumption can limit the progression of this “death front,” protecting a population from a nominally deadly antibiotic dose. While increasing nutrient supply can overcome this bottleneck, in some cases, excess nutrient unexpectedly promotes the regrowth of resistant cells. Altogether, this work provides a key step toward predicting and controlling antibiotic treatment of spatially structured bacterial populations, yielding biophysical insights into collective behavior and guiding strategies for effective antibiotic stewardship.
Additional Research:
Demirer Lab
Optimized R2 Retroelement Complexes for DNA Insertion Into Plant Genomes
Traditional approaches for DNA insertion into plant genomes using Agrobacterium tumefaciens result in random integration. Newer genetic engineering methods based on nucleases, prime editors, transposases and recombinases extend capabilities but remain constrained with low efficiencies, off-target integration or limited payload size. Here we adapt the avian Taeniopygia guttata R2 protein (R2Tg) for targeted DNA insertion into plant genomes by engineering R2Tg expression cassettes and RNA payloads carrying intron-disrupted reporters, with optimized ribosomal DNA homology arms and untranslated regions. In Arabidopsis thaliana protoplasts, Nicotiana benthamiana leaves and Solanum lycopersicum seedlings, our R2Tg editor system achieves targeted insertion of full-length payloads ranging from 2.2 kb to 5 kb. In Nicotiana benthamiana leaves, integration occurs, on average, at 1 copy per genome, which is 30 times more efficient than that achieved by Cas9 homology-directed repair. This work establishes an R2Tg ribonucleoprotein platform for targeted DNA insertion into plant genomes, using a multicopy genomic safe-harbor site to enable efficient addition of multikilobase genes.
Ismagilov Lab
A Train-and-Assist Device That Upskills Novices to Strengthen the Workforce and Expand Diagnostic Access
AI and automation technologies are displacing millions of workers across industries in developed countries, while many developing nations continue to grapple with chronically high unemployment. Meanwhile, healthcare laboratories—particularly in resource-limited settings (including rural and community sites within high-income countries)—face acute shortages of trained staff and the high cost of molecular diagnostics. Here, we propose a “train-and-assist” class of devices that aims to both (i) upskill—rather than replace—workers and (ii) expand diagnostic capacity in a cost-effective way. We describe a device that trains and assists laboratory-inexperienced personnel to perform sample-pooling procedures, which enable high-performance molecular testing at lower costs and higher throughput. A 48-participant user study demonstrated that the device enabled both skill acquisition and high-accuracy pooling. A device-validation study using clinical stool specimens demonstrated that device-assisted pooling agreed 100% with individual assays for soil-transmitted helminths, which affect >1.5 billion people worldwide.
Manthiram Lab
Direct Electrochemical Propylene Epoxidation Over Amorphized Perovskite Oxide in Non-halogenated Aqueous Electrolyte
Industrial routes for propylene oxide and propylene glycol production involve either explosive hydrogen peroxide or corrosive chlorine-containing reagents, which produce hazardous halogenated by-products. Direct aqueous electrooxidation is a safe and sustainable alternative that uses water as an oxygen source at a catalytically competent anode. Until now, the direct aqueous route has only been demonstrated on noble metals (Pd, Pt, Au, Ag), which are unstable unless operated in halogenated electrolytes. Here we have developed a noble metal- and halogen-free catalytic system using a cobalt-based perovskite oxide with a Faradaic efficiency of 40% toward propylene oxide and propylene glycol, maintained over 24 h of operation. Kinetic analysis revealed potential-dependent rate-limiting steps involving electrochemical oxygen species generation and thermochemical oxygen transfer to propylene. This work establishes a cost-effective and safe synthetic route with earth-abundant non-noble metal-based catalysts, not only for propylene epoxidation but also for other heterogeneous oxygen-transfer reactions.
Peters Group
A Synthetic Iron Model of Carbon–Sulfur Bond Activation by the Nitrogenase-Family Enzyme Methylthio-Alkane Reductase
The all-iron (FeFe) nitrogenase utilizes a complex iron–sulfur cluster to catalyze the reduction of dinitrogen to ammonia (N2R). Recently, it has been found that methylthio-alkane reductase (mar), which reduces methyl thioalkanes to methanethiol and hydrocarbon fragments, has a structurally similar active site. In this report, we explore the reactivity of a trisphosphine boratrane iron complex ([Fe]), an N2R catalyst, with thioalkanes as a functional model system. Reacting the neutral iron dinitrogen complex ([Fe(N2)]) with dimethyl sulfide (Me2S) yields a 1:1 mixture of iron methyl ([FeMe]) and iron methyl thiolate ([Fe(SMe)]) products. Subsequent protonation forms methane and methanethiol, the products of Me2S reduction by mar. Kinetic studies, including kinetic isotope effects (KIE), pre-equilibrium Van’t Hoff parameters, and Eyring analysis, as well as the reactivity with a broad scope of thioalkanes, point to [Fe(SMe2)], formed via an uphill pre-equilibrium with [Fe(N2)] as a key intermediate. In [Fe(SMe2)], the C–S bond strength decreases by 44 kcal mol–1, priming it for bond homolysis. We propose that homolytic C–S bond cleavage occurs with the released alkyl radical being trapped by a second equivalent of iron. Comparisons of N2 and thioalkane reduction by [Fe] suggest similar modes of substrate activation at Fe, namely, backbonding into a π* orbital of N≡N and a C–S σ* orbital of Me2S, setting the substrates up for N–H bond formation and homolytic C–S bond cleavage, respectively.
Peters Group and Reisman Lab
Photodriven Sm-Catalyzed Asymmetric Ketyl-Olefin Coupling
SmI2 is a privileged, single-electron reductant employed in the synthesis of diverse products. Though traditionally used in (super)stoichiometric amounts, SmI2 has recently been employed catalytically with viable turnover strategies. Enantioselective reductive cross-coupling reactions mediated by SmI2 are scarce and asymmetric methods that use catalytic quantities of SmI2 are unknown. Herein, we report an enantioselective ketyl-olefin coupling, employing a SmI2-derived catalyst with a widely available chiral pyridine-bis(oxazoline) (PyBOX) ligand and a commercially available Ir photocatalyst. A combination of optical, electrochemical, and computational data reveals that a Sm-stabilized PyBOX radical is the reactive species responsible for initiating the reductive coupling step.