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L‐asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

Glutamate is an important signaling molecule in the nervous system and its extracellular levels are regulated by amino acid transporters. Studies on the role of glutamate transport have benefitted from the development of small molecule inhibitors. Most inhibitors, however, cannot be remotely controlled with respect to the time and place of their action, which limits their application in biological studies. Herein, the development and evaluation of inhibitors of the prokaryotic transporter Glt Tk with photo-controlled activity, enabling the remote, reversible, and spatiotemporally resolved regulation of transport is reported. Based on a known inhibitor, seven inhibitors, bearing a photoswitchable azobenzene moiety, are designed and synthesized. The most promising photo-controlled inhibitor, shows in its non-irradiated form, an IC 50 of 2.5 ± 0.4 μm for transport by Glt Tk . Photoswitching results in a reversible drop of potency to an IC 50 of 9.1 ± 1.5 μm. This 3.6-fold difference in activity is used to demonstrate that the transporter function can be switched on and off reversibly through irradiation. As a result, this inhibitor could be a powerful tool in studying the role of glutamate transport by precisely controlling the time, and the specific tissue or groups of cells, in which the inhibitor is active.

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G+) and Gram-negative (G−) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G+ and G− strains with MIC values of 0.125–8 μg/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action.