Rationale Effort-related motivational symptoms such as anergia and fatigue are common in patients with depression and other disorders. Research implicates pro-inflammatory cytokines in depression, and administration of cytokines can induce effort-related motivational symptoms in humans. Objectives The present experiments focused on the effects of the pro-inflammatory cytokine interleukin 1-beta (IL-1β) on effort-related choice behavior. Methods Rats were tested on a concurrent fixed ratio 5 lever pressing/chow feeding choice procedure, which assesses the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (laboratory chow). Results IL-1β (1.0–4.0 μg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing intake of the freely available chow. The second experiment assessed the ability of the adenosine A2A antagonist MSX-3 to reverse the behavioral effects of IL-1β. MSX-3 attenuated the effort-related impairments produced by IL-1β, increasing lever pressing and also decreasing chow intake. In the same dose range that shifted effort-related choice behavior, IL-1β did not alter food intake or preference in parallel free-feeding choice studies, indicating that these low doses were not generally suppressing appetite or altering preference for the high carbohydrate pellets. In addition, IL-1β did not affect core body temperature. Conclusions These results indicate that IL-1β can reduce the tendency to work for food, even at low doses that do not produce a general sickness, malaise, or loss of appetite. This research has implications for the involvement of cytokines in motivational symptoms such as anergia and fatigue.

Highlights d Inhibitors of the folate pathway in Mycobacterium tuberculosis have been identified d These molecules are dual inhibitors of dihydrofolate reductase and Rv2671 d para-Aminosalicylic acid metabolite inhibits flavindependent thymidylate synthase d Antifolates decrease the level of precursors of mycolic acids in M.

The folate cycle is one of the key metabolic pathways used by bacteria to synthesize vital building blocks required for proliferation. Therapeutic agents targeting enzymes in this cycle, such as trimethoprim and sulfamethoxazole, are among some of the most important and continually used antibacterials to treat both Gram-positive and Gram-negative pathogens. As with all antibacterial agents, the emergence of resistance threatens the continued clinical use of these life-saving drugs. In this article, we describe and analyze resistance mechanisms that have been clinically observed and review newer generations of preclinical compounds designed to overcome the molecular basis of the resistance.

Enolase is a glycolytic metalloenzyme involved in carbon metabolism. The advantage of targeting enolase lies in its essentiality in many biological processes such as cell wall formation, RNA turnover and as a plasminogen receptor. We initially used a DARTS assay to identify enolase as a target in Escherichia coli. The antibacterial activity of α-, β-, and γ-substituted seven-member ring tropolones were first evaluated against four strains representing a range of Gram-negative bacteria. We observed that the chemical properties and position of the substituents on the tropolone ring plays an important role in the biological activity of the investigated compounds. Both αand βsubstituted phenyl derivatives of tropolone were the most active with MIC values in the range of 11-14μg/mL. The potential inhibitory activity of the synthetic tropolones was further evaluated using an enolase inhibition assay, X-ray crystallography and molecular docking simulations. The catalytic activity of enolase was effectively inhibited by both the naturally occurring p-thujaplicin and αand βsubstituted phenyl derivatives of tropolones with IC 50 values in range of 8 to 11 μM. Ligand binding parameters were assessed by ITC and DSC techniques and agreed with the in vitro data. Our studies validate the antibacterial potential of tropolones with careful consideration of position and character of chelating moieties for stronger interaction with metal ions and residues in the enolase active site.

The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit *