Cinacalcet exhibits rapid bactericidal and efficient anti-biofilm activities against multidrug-resistant Gram-positive pathogens.

Infections caused by Gram-positive bacteria pose a serious threat to global public health. Drug resistance, dormant persister cells, and biofilm formation are the key challenges affecting the efficacy of antibiotics against Gram-positive bacterial infections. In this study, cinacalcet exhibited good inhibitory activity against multidrug-resistant Gram-positive bacteria, with minimum inhibitory concentrations (MICs) ranging from 3.13 µg/mL to 25 µg/mL. Cinacalcet displayed more rapid and stronger bactericidal activity against planktonic and persister cells of Staphylococcus aureus and Enterococcus faecalis compared with the antibiotics vancomycin or ampicillin, as well as potent inhibition and eradication of mature biofilms of methicillin-resistant S. aureus (MRSA) and linezolid-resistant E. faecalis (LRE). In addition, the robust antibacterial activity was demonstrated in vivo by a pneumonia infection model and a biofilm formation and deep-seated infection model. Collectively, these findings indicate that cinacalcet may be a promising new candidate antibiotic to combat infections caused by multidrug-resistant Gram-positive pathogens.

Thiazolopyrimidinone Derivative H5-23 Enhances Daptomycin Activity against Linezolid-Resistant Enterococcus faecalis by Disrupting the Cell Membrane.

The increasing emergence and dissemination of multidrug-resistant (MDR) Gram-positive pathogens pose a serious threat to global public health. Previous reports have demonstrated that the compound H5-23, which has a thiazolopyrimidinone core structure, exhibited antibacterial activity against Staphylococcus epidermidis in vitro. However, the antibacterial activity in vivo and mechanism of action of H5-23 against MDR bacteria have not been fully studied. In this study, we report that H5-23 has wide-spectrum antibacterial activity against Gram-positive bacteria. When combined with daptomycin (DAP), H5-23 demonstrates enhanced antimicrobial activity, effectively killing both planktonic and persister cells, as well as eradicating biofilm formation by linezolid-resistant Enterococcus faecalis. The development of resistance shows that H5-23 has a low propensity to induce antibiotic resistance compared to that of linezolid in vitro. Mechanistic studies reveal that H5-23 increases membrane permeability and disrupts membrane integrity, resulting in increased production of reactive oxygen species (ROS), metabolic perturbations, and ultimately cell death. Additionally, we demonstrate the synergistic antibacterial effect of H5-23 combined with DAP in a murine model. These findings suggest that H5-23 is a promising antimicrobial agent and provides a potential strategy for enhancing the efficacy of DAP in combating multidrug-resistant E. faecalis.

Inhibition of planktonic growth and biofilm formation of Staphylococcus aureus by entrectinib through disrupting the cell membrane.

Over the last few decades, Staphylococcus aureus infection remain a major medical challenge and health concern worldwide. Biofilm formation and antibiotic resistance caused by S. aureus make it difficult to be eradicated from bacterial infections in clinics. In this study, our data demonstrated the antibacterial and excellent anti-biofilm activity of entrectinib against S. aureus. Entrectinib also exhibited the good safety, suggesting no toxicity with antibacterial concentration of entrectinib toward the erythrocytes and mammalian 239 T cells. Moreover, entrectinib significantly reduced the bacterial burden of septic tissue in a murine model of MRSA infection. Global proteomic analysis of S. aureus treated with entrectinib showed significant changes in the expression levels of ribosomal structure-related (rpmC, rpmD, rplX, and rpsT) and oxidative stress-related proteins (Thioredoxin system), suggesting the possible inhibition of bacterial protein biosynthesis with entrectinib exposure. The increased production of reactive oxygen species (ROS) was demonstrated in the entrectinib-treated S. aureus, supported the impact of entrectinib on the expression changes of ROS-correlated proteins involved in oxidative stress. Furthermore, entrectinib-induced resistant S. aureus clone was selected by in vitro induction under entrectinib exposure and 3 amino acid mutations in the entrectinib-induced resistant S. aureus strain, 2 of which were located in the gene encoding Type II NADH: quinoneoxidoreductase and one were found in GTP pyrophosphokinase family protein. Finally, the bactericidal action of entrectinib on S. aureus were confirmed by disrupting the bacterial cell membrane. Conclusively, entrectinib exhibit the antibacterial and anti-biofilm activity by destroying cell membrane against S. aureus.

The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Homeostasis.

With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 µg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

Pubertal maturation and weight status are associated with dyslipidemia among children and adolescents in Northwest China.

Dyslipidemia is one of major risk factors for cardiovascular disease. The early detection and treatment of dyslipidemia can reduce cardiovascular disease risk. A cross-sectional study was carried out in Ningxia, China to determine the prevalence of dyslipidemia and its association with body mass index (BMI) and pubertal stage. A total of 1783 students were selected from middle schools and high schools in September 2014 using stratified random cluster sampling. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured by using MOL-300 automatic biochemical analyzer with associated kits. The prevalence of adolescents with one abnormal serum lipid component was 43.2% and was significantly different across three pubertal stages (p < 0.0001). The abnormal rates of HDL-C and TG increased as the students maturated through the early, middle, and late stages of puberty (all p < 0.0001). Similar results were obtained when separate analyses were performed for boys and girls. In linear regression analysis, BMI was positively associated with serum levels of TC, LDL-C, and TG, but inversely associated with serum levels of HDL-C after the adjustment for age, sex, and race. In multivariable logistic regression analysis, obesity was associated with an increased risk of developing high TC, while pubertal maturation was associated with an elevated risk of experiencing low HDL-C and high TG (all p < 0.05). In conclusions, dyslipidemia is common in an adolescent population of Northwest China and its prevalence rates substantially vary with weight status and pubertal stage.

Serum 25-hydroxyvitamin D and bone mineral density among children and adolescents in a Northwest Chinese city.

Although vitamin D is essential for bone health, little is known about prevalence of vitamin D deficiency and low bone mineral density (BMD) among children, especially those in developing countries. It also remains unclear whether serum 25-hydroxyvitamin D [25(OH)D] is associated with BMD among children. We investigated these questions among children and adolescents in Yinchuan (latitude: 38°â€¯N), Ningxia, an economically underdeveloped province in Northwest China. A total of 1582 children (756 boys and 826 girls), aged 6-18 years, were recruited from schools using the stratified random sampling method in fall 2015. Serum 25(OH)D concentrations were measured by enzyme-linked immunosorbent assay, and BMD was quantified by dual-energy X-ray absorptiometry. Vitamin D deficiency (defined as serum 25(OH)D ≤ 37.5 nmol/L) was present in 35.5% of study subjects. There were no clear patterns of differences in serum 25(OH)D concentrations across the four age groups compared (6-9 years, 10-13 years, 14-16 years, and 17-18 years). The prevalence of low total body less head (TBLH) BMD (defined as a Z-score of ≤ -2.0 standard deviations away from the mean BMD values of the Chinese pediatric reference population) among children examined was 1.8% and was not significantly different among the four age groups considered. Linear regression analysis revealed that age, weight, and height were significantly and positively associated with TBLH BMD and that the strongest determinant of TBLH BMD was age in boys and weight in girls. There were no significant correlations between serum 25(OH)D concentrations and BMD obtained for total body and at various skeletal sites (r ranged from -0.005 to 0.014) regardless of whether children evaluated were sufficient, insufficient, or deficient in vitamin D. In conclusion, more than one-third of children and adolescents in a Northwest Chinese city were deficient in vitamin D but only <2% of them developed low BMD.