Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Hypericin enhances -lactam antibiotics activity by inhibiting expression in methicillin-resistant

Bacteremia is a life-threating syndrome often caused by methicillin-resistant (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and -lactam antibiotic resistance in . Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on -lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of -lactam antibiotics (.., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced expression, and subsequently decreased and virulence-related regulators (.., ) and genes (.., and ) expression in the studied MRSA strain. Importantly, the synergistic effect of hypericin with -lactam antibiotic (.., oxacillin) translated into therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of -lactam resistance against MRSA through inhibition, and may allow us to repurpose the use of -lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (.., oxacillin).

and activity of d-serine in combination with -lactam antibiotics against methicillin-resistant

As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate and activity of d-serine alone and in combination with -lactams against methicillin-resistant (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, -lactams alone and in combinations was evaluated both by standard MICs, time-kill curves and checkerboard assays, and by murine systemic infection model as well as neutropenic thigh infection model. An synergistic effect was demonstrated with the combination of d-serine and -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to -lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with -lactams against MRSA strains both and . Considering the relatively good safety of d-serine alone or in combination with -lactams, d-serine is worth following up as new anti-MRSA infection strategies.

Repair of bedsore over greater trochanter in paraplegic patients with rectus femoris island myocutaneous flap / 中华烧伤杂志

<p><b>OBJECTIVE</b>To observe the effect of rectus femoris island myocutaneous flap for repairing bedsores in III and IV phases at the femoral greater trochanter area as a result of paraplegia.</p><p><b>METHODS</b>Thirteen paraplegic patients who suffered bedsores in III and IV phases at the greater trochanter of femur area were hospitalized from July 2009 to June 2013. The bedsores ranged from 4.5 cm×4.0 cm to 10.0 cm× 9.0 cm in area. After debridement, the size of soft tissue defect ranged from 5.0 cm×4.5 cm to 10.5 cm×10.0 cm. Rectus femoris island myocutaneous flaps were used to repair these defects, with flap area ranging from 5.0 cm×5.0 cm to 11.0 cm×10.0 cm and muscular pedicle length ranging from 8 to 12 cm. The donor sites of muscular pedicle were closed by direct suture, while those resulted from forming myocutaneous flap were closed by the transplantation of autologous skin obtained from thigh.</p><p><b>RESULTS</b>Necrosis appeared at the edge of myocutaneous flap in one patient, and it was healed after dressing change. The other 12 myocutaneous flaps survived well. Patients were followed up for 2 to 30 months, and bedsore did not recur.</p><p><b>CONCLUSIONS</b>Rectus femoris island myocutaneous flap, with characteristics of reasonable design, large donor area, big rotation angle, and with wear-, tear-, and pressure-resistance, is suitable for repairing bedsores at III and IV phases at the greater trochanter of femur area in paraplegic patients.</p>

Genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii from Beijing, China

The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing, China. 173 A. baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance (HLAR, MIC to gentamicin and amikacin>512 µg/mL) phenotype selection by broth microdilution method. The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes (aac(3)-I, aac(3)-IIc, aac(6')-Ib, aac(6')-II, aph(4)-Ia, aph(3')-I, aph(3')-IIb, aph(3')-IIIa, aph(3')-VIa, aph(2″)-Ib, aph(2″)-Ic, aph(2″)-Id, ant(2″)-Ia, ant(3″)-I and ant(4')-Ia) and the 16S rRNA methylase genes (armA, rmtB and rmtC). Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS. Totally 102 (58.96%) HLAR isolates were selected. The HLAR rates for year 2006, 2007, 2008 and 2009 were 52.63%, 65.22%, 51.11% and 70.83%, respectively. Five modifying enzyme genes (aac(3)-I, detection rate of 65.69%; aac(6')-Ib, detection rate of 45.10%; aph(3')-I, detection rate of 47.06%; aph(3')-IIb, detection rate of 0.98%; ant(3″)-I, detection rate of 95.10%) and one methylase gene (armA, detection rate of 98.04%) were detected in the 102 A. baumannii with aac(3)-I+aac(6')-Ib+ant(3″)-I+armA (detection rate of 25.49%), aac(3)-I+aph(3')-I+ant(3″)-I+armA (detection rate of 21.57%) and ant(3″)-I+armA (detection rate of 12.75%) being the most prevalent gene profiles. The values of chi-square tests showed correlation of armA, ant(3″)-I, aac(3)-I, aph(3')-I and aac(6')-Ib with HLAR. armA had significant correlation (contingency coefficient 0.685) and good contingency with HLAR (kappa 0.940). The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A. baumannii infections. As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides (gentamicin, amikacin, tobramycin, etc), the function of aminoglycoside modifying enzyme gene(s) in A. baumannii carrying armA deserves further investigation.

Effect of Brazilein on Relaxation of Vascular Smooth Muscle of Rat / 世界科学技术-中医药现代化

Brazilein is one of the active ingredients of a Chinese medicine Caesalpinia sappan L. This study was aimed to test the vasodilator effect of brazilein on vascular smooth muscle cells in vitro from the perspective of molecular biology. The results showed that brazilein mainly acted through the influence of potassium ion channels, reducing membrane depolarization in order to affect the vessel relaxation. This effect can be influenced by blocking 5-HT receptor, and, simultaneously, correlating with the regulation of intracellular calcium ion concentration, affecting calmodulin and downregulating MLCP. In addition, the alterations of cAMP, PKA and PGI2 were involved in the pharmacological process of brazilein.

Study on embryonic toxicity of Senecio scandens, Qianbai Biyanpian and total alkaloid from S. scandens in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the characteristics of embryonic toxicity of Senecio scandens, its total alkaloid and Qianbai Biyanpian so that to provide guidance for the safety of medication during pregnancy.</p><p><b>METHOD</b>Two hundred and twenty pregnant SD rats were divided into 11 groups: control group, positive group (cyclophosphamide 10 mg x kg(-1)). Water extract of S. scandens (doses: 7.5, 15.0, 30.0 g herb of S. scandens per kilogram body weight respectively). Qianbai Biyanpian and total alkaloid at the same doses levels with the water extract of S. scandens (doses were expressed as herb of S. scandens per kilogram body weight). The test articles were given to the pregnant rats by gavage from day 6 to day 15 of pregnancy. Body weight and the food consumption of pregnancy rats, and fetal weight and length were measured. The number of absorbed and dead embryos was recorded. Fetuses were examined in viscus and bones.</p><p><b>RESULT</b>Weight and the food consumption of pregnancy rats in high-dose of Qianbai Biyanpian and total alkaloids decreased. All treatment groups had no significant change in the number of absorbed embryos, but the stillbirths were significantly increased in high-dose groups of water extract and total alkaloids as compared with control group. Bone deformities such as fontanel expanding, hypoplasia of parietal bone, occipital bone and cervical arch were observed. Rib abnormality could also be seen in some rats. All water extract of S. scandens, Qianbai Biyanpian and total alkaloid could cause the bone abnormalities, but the percentage of bone deformities of total alkaloids was the highest (up to 80%).</p><p><b>CONCLUSION</b>S. scandens and its total alkaloids, its formula Qianbai Biyanpian can cause rat skeletal deformities in fetuses when they were given during pregnancy. It is suggested that S. scandens and the product containing S. scandens should not be used during pregnancy.</p>

Regulatory effects of Wuzhuyutang (Evodiae prescription) and its consisting herbs on TPH2 promoter / 中国中药杂志

<p><b>OBJECTIVE</b>To screen the active component of Wuzhuyutang (WZYT, Evodiae prescription) and investigate the regulatory effects of the components in WZYT on the TPH2 promoter, and to explore the possible molecular mechanism of WZYT on migraine.</p><p><b>METHOD</b>By transfecting a TPH2 promoter regulating Red Fluorescent Protein expressing plasmid into PC12 cell, the global fluorescence intensities and calculations of fluorescent cells after components treatment were statistically evaluated.</p><p><b>RESULT</b>Different regulatory effects of different components in WZYT with different concentrations on TPH2 promoter were observed.</p><p><b>CONCLUSION</b>TPH2 promoter drove Red Fluorescent Protein expressing cell line can be used as system screening components targeting TPH2 promoter activity. The possible mechanism of WZYT on migraine may due to its stimulating effects on TPH2 promoter, and promote the synthesis and release of 5-HT in cerebral.</p>