Sodium deoxycholate synergistically enhances the antimicrobial activity of β-lactam antibiotics againstβ-lactamase-producing Staphylococcus aureus

Background β-lactamase-producing Staphylococcus aureus synthesizes a β-lactamase which decomposes the β-lactam ring, and consequently almost all β-lactam antibiotics are inactivated by the enzyme. The appearance of β-lactamase-producing bacterial strains has diminished the usefulness of β-lactam antibiotics. New therapeutic agents or new approaches are urgently needed for drug-resistant bacteria. Objective We investigated the antimicrobial activity of sodium deoxycholate against β-lactamase- producing S. aureus strains, and the synergistic effects of sodium deoxycholate on the antimicrobial activity of β-lactam antibiotics against those strains. The possibility of this combination as a new therapeutic method against infectious diseases caused by β-lactamaseproducing bacteria was examined. Methods The synergistic effects of the combined use of sodium deoxycholate on the antimicrobial activities of β-lactam antibiotics against β-lactamase-producing S. aureus strains were tested by using an MIC (minimum inhibitory concentration) assay. The inhibitory effect of sodium deoxycholate on the β-lactamase activity was examined by nitrocefin assay. Results The antimicrobial activities of β-lactam antibiotics , including benzylpenicillin, ampicillin and piperacillin, against β-lactamase-producing S. aureus strains were obviously enhanced by the combination with sodium deoxycholate. In addition, it was demonstrated that sodium deoxycholate remarkably eliminated the synthesis of β-lactamase in β-lactamase-lactamaseproducing S. aureus. Conclusion The combined use of sodium deoxycholate with β-lactam antibiotic is expected to be a new therapeutic method and may contribute to an effective tilization of -lactam antibiotics against infectious diseases caused by β-lactamase-producing bacteria.背景　β-ラクタマーゼ産生黄色ブドウ球菌などが産生するβ-ラクタマーゼは、β-ラクタム系抗菌薬が有するβ-ラクタム環を開裂させることで、その抗菌活性を失活させる。そのため、β-ラクタマーゼ産生菌が原因となる感染症に対して、限られた薬剤しか使用できないのが現状である。Β-ラクタマーゼ産生菌などの多剤耐性菌による感染症に対し、新しい治療薬や治療方法の開発が急務となっている。　目的　界面活性作用のあるデオキシコー目的　界面活性作用のあるデオキシコール酸ナトリウムは、抗菌活性も有していることが知られている。本研究では、この化合物のβ-ラクタマーゼ産生黄色ブドウ球菌に対する抗菌活性、並びに同化合物とβ-ラクタム系抗菌薬とを併用した場合の、同細菌に対する抗菌活性相乗効果にっいて解析を行い、本化合物がβ-ラクタマーゼ産生細菌による感染症に対し、新しい治療薬・治療方法の開発に結び付く可能性について検討を行った。 方法　β-ラクタマーゼ産生黄色ブドウ球菌に対するデオキシコール酸ナトリウムの抗菌活性、および同化合物とβ-ラクタム系 (ペニシリン系) 抗菌薬とを併用した場合の抗菌活性相乗効果について、MIC (minimum　inhibitory　concentration) 法で解析した。また、デオキシコール酸ナトリウムによるβ-ラクタマーゼの酵素活性阻害作用、および同酵素の生合成阻害作用に関して、ニトロセフィンを用いた吸光度測定法で解析した。 結果　β-ラクタマーゼ産生黄色ブドウ球菌に対して、ほとんど抗菌活性を示さなかったペニシリン系抗菌薬が、デオキシコール酸ナトリウムと併用することで顕著な抗菌活性を示した。この抗菌活性の増強効果は、デオキシコール酸ナトリウムによる同細菌に対するβ-ラクタマーゼの生合成阻害作用によるものであることが強く示唆された。 結論　デオキシコール酸ナトリウムとβ-ラクタム系 (ペニシリン系) 抗菌薬との併用による抗菌活性相乗効果に関する研究は、β-ラクタマーゼ産生黄色ブドウ球菌などの多剤耐性菌が原因となる感染症に対し、全く新しい治療方法の開発や既存抗菌薬の有効利用等に結びつく可能性が期待される

Correlation between renal function and common risk factors for chronic kidney disease in a healthy middle-aged population: a prospective observational 2-year study.

Age, proteinuria, metabolic syndrome, and hyperuricemia are the reported risk factors for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the best predictor of changes in renal function in the early stages of renal disease in a healthy middle-aged population is still unknown. Our study evaluated the correlation between changes in renal function and common risk factors to determine such a predictor.In total, 2,853 healthy persons aged ≤50 years participated in the study. They had no proteinuria and were not on medications for hypertension, diabetes mellitus, hyperlipidemia, or hyperuricemia. Over 2 years, participants underwent annual health screening. The relationship between changes in estimated glomerular filtration rate (eGFR) and changes in risk factors for CKD was evaluated using univariate and multivariate linear regression analyses.Over 2 years, eGFR showed a significant decrease. Univariate regression analysis revealed that changes in fasting plasma glucose (FPG), total cholesterol, LDL-cholesterol, serum uric acid levels, and hemoglobin showed a significant negative correlation with changes in eGFR. Multiple regression analysis confirmed that changes in FPG, serum uric acid levels, in particular, and hemoglobin had a significant negative correlation with changes in eGFR.The changes in eGFR and other variables over 2 years were small and could be within expected biologic variation. A longer observational study is needed to elucidate whether FPG, serum uric acid and hemoglobin represent the earliest markers of eGFR decline

Prevalence of hyperuricemia (male, n = 1,515; female, n = 1,257).

<p>Hyperuricemia: serum uric acid ≥7 mg/dL in males and ≥6 mg/dL in females.</p><p>Prevalence of hyperuricemia (male, n = 1,515; female, n = 1,257).</p

Simple linear regression analysis of factors related to ΔeGFR.

<p>All values are expressed as mean ± SD.</p><p>Abbreviations and symbols: eGFR, estimated glomerular filtration rate; Δ, change in the variable over 2 years; β, standardized regression coefficient; MetS, metabolic syndrome; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; HbA_1c, hemoglobin A_1c; HDL, high density lipoprotein; LDL, low density lipoprotein; Hb, hemoglobin.</p><p>Simple linear regression analysis of factors related to ΔeGFR.</p

Characteristics of subjects at baseline and 2 years.

<p>All values are expressed as mean ± SD. <i>P</i> values: a, paired <i>t</i>-test; b, McNemar's test comparing baseline with 2 years.</p><p>Abbreviations and symbols: Δ, change in the variable over 2 years; 95% CI, 95% confidence interval; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; HbA_1c, hemoglobin A_1c; eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; LDL, low density lipoprotein; Hb, hemoglobin.</p><p>Characteristics of subjects at baseline and 2 years.</p