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Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections.

Introduction: Trophoblast-derived angiogenic factors are considered to play an important role in the pathophysiology of various complications of pregnancy. Human Leukocyte Antigen-G (HLA-G) belongs to the non-classical human major histocompatibility complex (MHC-I) molecule and has membrane-bound and soluble forms. HLA-G is primarily expressed by extravillous cytotrophoblasts located in the placenta between the maternal and fetal compartments and plays a pivotal role in providing immune tolerance. The aim of this study was to establish a relationship between concentrations of soluble HLA-G (sHLA-G) in maternal serum and amniotic fluid at 16–22 weeks of gestation and the sonographic measurements of fetal and placental growth. Materials and methods: sHLA-G in serum and amniotic fluid, as well as fetal biometric data and placental volume and perfusion indices, were determined in 41 singleton pregnancies with no complications. The level of sHLA-G (U/mL) was tested with a sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results: The sHLA-G levels were unchanged both in amniotic fluid and serum during mid-pregnancy. The sHLA-G level in serum correlated positively with amniotic sHLA-G level (β = 0.63, p < 0.01). Serum sHLA-G level was significantly correlated with abdominal measurements (β = 0.41, p < 0.05) and estimated fetal weight (β = 0.41, p < 0.05). Conversely, amniotic sHLA-G level and placental perfusion (VI: β = −0.34, p < 0.01 and VFI: β = −0.44, p < 0.01, respectively) were negatively correlated. A low amniotic sHLA-G level was significantly associated with nuchal translucency (r = −0.102, p < 0.05). Conclusions: sHLA-G assayed in amniotic fluid might be a potential indicator of placental function, whereas the sHLA-G level in serum can be a prognostic factor for feto-placental insufficiency.

The aim of the present study was to determine the effects of alcohol intoxication and withdrawal on hypothalamic neurohormones such as corticotropin-releasing factor (CRF) and arginine vasopressin (AVP), and extrahypothalamic neurotransmitters such as striatal dopamine (DA), amygdalar gamma aminobutyric acid (GABA), and hippocampal glutamate (GLU). In addition, the participation of the two CRF receptors, CRF1 and CRF2, was investigated. For this purpose, male Wistar rats were exposed to repeated intraperitoneal (ip) administration of alcohol every 12 h, for 4 days and then for 1 day of alcohol abstinence. On the fifth or sixth day, intracerebroventricular (icv) administration of selective CRF1 antagonist antalarmin or selective CRF2 antagonist astressin2B was performed. After 30 min, the expression and concentration of hypothalamic CRF and AVP, the concentration of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), and the release of striatal DA, amygdalar GABA, and hippocampal GLU were measured. Our results indicate that the neuroendocrine changes induced by alcohol intoxication and withdrawal are mediated by CRF1, not CRF2, except for the changes in hypothalamic AVP, which are not mediated by CRF receptors.