Novel humanized anti-PcrV monoclonal antibody COT-143 protects mice from lethal Pseudomonas aeruginosa infection via inhibition of toxin translocation by the type III secretion system.

Treatment of Pseudomonas aeruginosa infection is challenging due to its intrinsic and acquired antibiotic resistance. As the number of current therapeutic options for P. aeruginosa infections is limited, developing novel treatments against the pathogen is an urgent clinical priority. The suppression of virulence of P. aeruginosa could be a new therapeutic option, and the type III secretion system (T3SS), which enables the bacteria to translocate various kinds of toxins into host cells and inhibits cellular functions, is considered as one possible target. In this report, we examined T3SS inhibition by COT-143/INFEX702, a humanized monoclonal antibody against PcrV, T3SS component, and present the crystal structure of the antibody-PcrV complex. COT-143 inhibited T3SS-dependent cytotoxicity and protected mice from the mortality caused by P. aeruginosa infection. The inhibition of cytotoxicity coincided with inhibition of translocon formation in a host cell membrane, which is necessary for T3SS intoxication. COT-143 protected murine neutrophils and facilitated phagocytosis of P. aeruginosa. These results suggest that COT-143 facilitates P. aeruginosa clearance by protecting neutrophil via inhibition of T3SS-dependent toxin translocation. This is the first report to show that an anti-PcrV antibody directly interferes with translocon formation to inhibit intoxication of host cells.

Butterfly needle tap and suction (BTS) technique: a treatment for recurrent chronic subdural hematoma after burr hole craniostomy.

BACKGROUND: In this study, we propose a butterfly needle tap and suction (BTS) technique for recurrent chronic subdural hematoma (CSDH) as an alternative to reoperation with burr hole craniostomy (BHC) and investigate its efficacy and safety. The procedure involves percutaneous puncture through the burr hole created during the previous surgery and subsequent hematoma evacuation using a butterfly needle. METHODS: This retrospective study included patients who underwent BTS for CSDH at Ogaki Municipal Hospital between January 2017 and December 2020. The follow-up CT scans were reviewed after several weeks. We evaluated the number of percutaneous punctures required to resolve CSDH during the BTS technique, the volume of the evacuated hematoma, and procedure-related complications. RESULTS: Twenty-six patients were enrolled in the study, 21 of whom achieved resolution of the hematoma using punctures with the BTS technique alone (mean, 2.2 ± 1.5). Five patients had a recurrence of hematoma after one or more punctures during the BTS technique, and they underwent reoperation with BHC according to the surgeon's decision or patient requests. Among the 55 punctures, 43.0 ± 16.0 ml of hematoma was evacuated per puncture. The evacuated hematoma volume was 41.9 ± 16.4 ml in the BTS-alone group and 49.4 ± 12.9 ml in the reoperation group, with no significant difference (p = 0.25). Three patients complained of a headache during the puncture procedure, and no other complications, including intracranial hemorrhage or infection, were reported therein. CONCLUSIONS: The BTS technique is an effective alternative to reoperation with BHC.

Contributions of yap1 Mutation and Subsequent atrF Upregulation to Voriconazole Resistance in Aspergillus flavus.

Aspergillus flavus is the second most significant pathogenic cause of invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure of A. flavus to subinhibitory concentrations of VRC in vitro causes the emergence of a VRC-resistant mutant with a novel resistance mechanism. The VRC-resistant mutant shows a MIC of 16 µg/ml for VRC and of 0.5 µg/ml for itraconazole (ITC). Whole-genome sequencing analysis showed that the mutant possesses a point mutation in yap1, which encodes a bZIP transcription factor working as the master regulator of the oxidative stress response, but no mutations in the cyp51 genes. This point mutation in yap1 caused alteration of Leu558 to Trp (Yap1Leu558Trp) in the putative nuclear export sequence in the carboxy-terminal cysteine-rich domain of Yap1. This Yap1Leu558Trp substitution was confirmed as being responsible for the VRC-resistant phenotype, but not for that of ITC, by the revertant to Yap1wild type with homologous gene replacement. Furthermore, Yap1Leu558Trp caused marked upregulation of the atrF ATP-binding cassette transporter, and the deletion of atrF restored susceptibility to VRC in A. flavus These findings provide new insights into VRC resistance mechanisms via a transcriptional factor mutation that is independent of the cyp51 gene mutation in A. flavus.

[A Case of Dural Arteriovenous Fistula that Developed 21 Months after Cerebral Venous Sinus Thrombosis].

A 56-year-old man experienced a sudden onset of left hemiparesis. The computed tomography(CT)scan revealed a lobar hemorrhage in the right fronto-parietal lobe. After his admission, deep vein thrombosis was detected in his left lower limb, and angiograms taken on the 36th day of hospitalization revealed cerebral venous sinus thrombosis. Anticoagulant treatment was induced. After 21 months, he experienced a sudden onset of left hemiparesis again. The CT scan revealed a new lobar hemorrhage in the right frontal lobe, and angiograms revealed that two dural arteriovenous fistulas(dAVF)developed in the superior sagittal sinus(SSS)and the left transverse-sigmoid sinus. The one in the SSS had retrograde drainage from the bilateral middle meningeal artery, and we performed transarterial embolization with 50% n-butyl-cyanoacrylate. Postoperative course was uneventful and no further stroke occurred. Intracranial dAVF is known to be an acquired disease caused by venous hypertension, but we rarely find new development of dAVFs after venous diseases. This patient's case will help to elucidate the pathophysiology of dAVF.

Antisense peptide nucleic acid­peptide conjugates for functional analyses of genes in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most common and clinically important pathogens because of its resistance to a wide variety of antibiotics. A number of treatments of P. aeruginosa have been developed, but there is still no definitive one. Antisense drugs have a great potential to treat multidrug-resistant P. aeruginosa because this technology, in principle, can inhibit the expression of any essential genes. Nucleic Acid Ther.2012, 22, 323 reported that peptide nucleic acid (PNA) antisenses conjugated to the carrier peptide (RXR)4 and targeted to ftsZ and acpP (essential genes) had antibacterial activity in P. aeruginosa. However, growth inhibition was also found with peptide-PNA antisense conjugates of mismatched sequences (negative controls), and hence there remains a possibility for considerable enhancement of basal level activity due to the general toxicity. To assess the true potential of peptide-PNA conjugates, we measured sequence-dependent knockdown of the (RXR)4-PNA conjugates by using a scrambled sequence as a negative control. In addition, we evaluated (RXR)4-PNA antisenses against three other essential genes (lepB, lptD and mraY) and a non-essential gene (PA1303), and confirmed that multiple sequences targeting only the essential genes showed antimicrobial activity in P. aeruginosa PAO1 cells. We also conducted a rescue experiment and confirmed that the antimicrobial activity of anti-mraY antisenses was an on-target effect, not due to general toxicity. These findings indicate that the (RXR)4­PNA antisense should be a useful tool for target validation of a specific gene and could be a therapeutic platform capable of targeting a variety of genes in P. aeruginosa.

Comparison of the risk of acquiring in vitro resistance to doripenem and tazobactam/piperacillin by CTX-M-15-producing Escherichia coli.

To compare the risk of acquiring in vitro resistance between doripenem and tazobactam/piperacillin by CTX-M-15-producing Escherichia coli, the in vitro frequency of resistance was determined. Four strains carrying multiple ß-lactamases such as blaOXA-1 or blaCTX-M-27 as well as blaCTX-M-15 and blaTEM-1 were used. No resistant colonies appeared on doripenem-containing plates, whereas resistant colonies were obtained from three of four test strains against tazobactam/piperacillin using agar plate containing 8- to 16-fold MIC of each drug. These three acquired tazobactam/piperacillin-resistant strains were not cross-resistant to doripenem, and they showed 1.9- to 3.1-fold higher piperacillin-hydrolysis activity compared to those of each parent strain. The change of each ß-lactamase mRNA expression measured by real-time PCR varied among three resistant strains. One of three tazobactam/piperacillin-resistant strains with less susceptibility to ceftazidime overexpressed both blaCTX-M-15 and blaTEM-1, and the other two strains showed higher mRNA expression of either blaTEM-1 or blaOXA-1. These results demonstrate that multiple ß-lactamases carried by CTX-M-15-producing E. coli contributed to the resistance to tazobactam/piperacillin. On the other hand, these resistant strains maintained susceptibility to doripenem. The risk of acquiring in vitro resistance to doripenem by CTX-M-15-producing E. coli seems to be lower than that to tazobactam/piperacillin.

Prevalence and molecular characterization of CTX-M extended-spectrum ß-lactamase-producing Escherichia coli from 2000 to 2010 in Japan.

The prevalence of extended-spectrum ß-lactamase (ESBL) in Enterobacteriaceae has been increasing worldwide. The aims of this study were to determine the prevalence of ESBLs among clinical isolates of Escherichia coli obtained from 2000 to 2010 in Japan, and to characterize the sequence type (ST) and antimicrobial susceptibility of the bla(CTX-M)-carrying strains. The genes for ß-lactamases were determined by conventional PCR and sequencing, and the antimicrobial susceptibility test was performed by the broth microdilution method. Among the 948 strains, 35 were judged as ESBL-positive strains. The positive rates ranged from 0.6% to 3.9% until 2008, but surged to 10.3% in 2010. Thirty-three of them carried bla(CTX-M), but all were negative for ESBL-type bla(TEM) and bla(SHV). bla(CTX-M-14) was the most prevalent (18/33) among bla(CTX-M)-carrying strains, followed by bla(CTX-M-15) (7/33) of which five were isolated in 2008 and 2010. Additionally, bla(CTX-M-27) appeared in 2010 for the first time in this study and accounted for more than a third of the bla(CTX-M)-carrying strains. From the MLST analysis, ST131 known as a world pandemic clone, has been predominantly isolated since 2006. The major types of ESBLs carried by ST131 strains clearly shifted from bla(CTX-M-14) to bla(CTX-M-15) and/or bla(CTX-M-27) between 2006 and 2010. Most of these isolates were still susceptible to doripenem, latamoxef (moxalactam), flomoxef and cefmetazole. Our results suggest that a change of the dominant type of ESBL among Enterobacteriaceae is currently in progress in Japan, and therefore further periodic surveillance is needed.

Binding properties of antimicrobial agents to dipeptide terminal of lipid II using surface plasmon resonance.

We developed a surface plasmon resonance (SPR) assay to estimate the interactions of antimicrobial agents with the dipeptide terminal of lipid II (D-alanyl-D-alanine) and its analogous dipeptides (L-alanyl-L-alanine and D-alanyl-D-lactate) as ligands. The established SPR method showed the reproducible immobilization of ligands on sensor chip and analysis of binding kinetics of antimicrobial agents to ligands. The ligand-immobilized chip could be used repeatedly for at least 200 times for the binding assay of antimicrobial agents, indicating that the ligand-immobilized chip is sufficiently robust for the analysis of binding kinetics. In this SPR system, the selective and specific binding characteristics of vancomycin and its analogs to the ligands were estimated and the kinetic parameters were calculated. The kinetic parameters revealed that one of the remarkable binding characteristics was the specific interaction of vancomycin to only the D-alanyl-D-alanine ligand. In addition, the kinetic binding data of SPR showed close correlation with the antimicrobial activity. The SPR data of other antimicrobial agents (e.g., teicoplanin) to the ligands showed correlation with the antimicrobial activity on the basis of the therapeutic mechanism. Our SPR method could be a valuable tool for predicting the binding characteristics of antimicrobial agents to the dipeptide terminal of lipid II.

Binding properties of antimicrobial agents to lipid membranes using surface plasmon resonance.

In the present study, we examined the interaction of antimicrobial agents with four model lipid membranes that mimicked mammalian cell membranes and Gram-positive and -negative bacterial membranes and analyzed the binding kinetics using our surface plasmon resonance (SPR) technique. The selective and specific binding characteristics of antimicrobial agents to the lipid membranes were estimated, and the kinetic parameters were analyzed by application of a two-state reaction model. Reproducible analysis of binding kinetics was observed. Vancomyicn, teicoplanin, erythromycin, and linezolid showed little interaction with the four lipid membranes in the SPR system. On the other hand, vancomycin analogues showed interaction with the model lipid membranes in the SPR system. The selective and specific binding characteristics of vancomycin analogues to the lipid membranes are discussed based on data for in vitro antibacterial activities and our data on the binding affinity of the D-alanyl-D-alanine terminus of a pentapeptide cell wall obtained by SPR. The mechanism of antibacterial activity against Staphylococcus aureus and vancomycin-resistant enterococci could be evaluated using the binding affinity obtained with our SPR techniques. The results indicate that the SPR method could be widely applied to predict binding characteristics, such as selectivity and specificity, of many antimicrobial agents to lipid membranes.

[A case of moyamoya disease with a subarachnoid hemorrhage treated with endovascular technique].

We report a case of a moyamoya disease presenting with subarachonoid hemorrhage (SAH) due to a ruptured aneurysm. A 40-year-old woman presented with sudden onset of headache and vomiting. Computed tomography (CT) showed diffuse thick SAH localized around basal cistern. 3D-CT Angiography (3D-CTA) and digital subtraction angiography (DSA) demonstrated a saccular aneurysm at the bifurcation of the left superior cerebellar artery and basilar artery. In addition, the both carotid arteries were occluded at the terminal portion and the territory of both middle cerebral arteries were perfused by abnormal moyamoya vessels. The aneurysm was completely embolized by endovascular embolization. The SAH due to a ruptured aneurysm associated with moyamoya disease is rare. We think endovascular therapy is safe and effective. However, a vasospasm of the catheter technique occurred during the operation. This fact is very important to consider when we treat diseases such as this in the future.

Large superconducting diode effect in ion-beam patterned Sn-based superconductor nanowire/topological Dirac semimetal planar heterostructures.

High-quality superconductor/topological material heterostructures are highly desired for realisation of topological superconductivity and Majorana physics. Here, we demonstrate a method to directly draw nanoscale superconducting ß-Sn patterns in the plane of a topological Dirac semimetal (TDS) α-Sn thin film by irradiating a focused ion beam and taking advantage of the heat-driven phase transition of α-Sn into superconducting ß-Sn. The ß-Sn nanowires embedded in a TDS α-Sn thin film exhibit a large superconducting diode effect (SDE), whose rectification ratio η reaches a maximum of 35% when the magnetic field is applied parallel to the current. The results suggest that the SDE may occur at the α-Sn/ß-Sn interfaces where the TDS α-Sn becomes superconducting by a proximity effect. Our work thus provides a universal platform for investigating quantum physics and devices based on topological superconducting circuits of any shape.

SPECT Imaging of P. aeruginosa Infection in Mice Using 123I-BMIPP.

Pseudomonas aeruginosa infection is an infectious disease that must be controlled because it becomes chronic and difficult to treat, owing to its unique system of toxin production/injection and elimination of other bacteria. Here, we noninvasively monitored P. aeruginosa using single-photon emission computed tomography (SPECT) imaging. Determining the amount and localization of the P. aeruginosa will enable making faster clinical diagnoses and selecting the most appropriate therapeutic agents and methods. Nonclinically, this information can be used for imaging in combination with biofilms and toxin probes and will be useful for discovering drugs targeting P. aeruginosa. To study P. aeruginosa accumulation, we conducted in vitro and in vivo studies using iodine-123 ß-methyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP), which we previously reported using for Escherichia coli. In vitro, 123I-BMIPP accumulated in P. aeruginosa by being taken up into the bacteria and adsorbing to the bacterial surface. In vivo, 123I-BMIPP accumulated significantly more in infected sites than in noninfected sites and could be quantified by SPECT. These results suggest that 123I-BMIPP can be used as a probe for P. aeruginosa for SPECT. Establishing a noninvasive monitoring method using SPECT will allow further progress in studying P. aeruginosa.

Efficacy of intraoperative irrigation with artificial cerebrospinal fluid in chronic subdural hematoma surgery: study protocol for a multicenter randomized controlled trial.

BACKGROUND: The surgical techniques for treatment of chronic subdural hematoma (CSDH), a common neurosurgical condition, have been discussed in a lot of clinical literature. However, the recurrence proportion after CSDH surgery remains high, ranging from 10 to 20%. The standard surgical procedure for CSDH involves a craniostomy to evacuate the hematoma, but irrigating the hematoma cavity during the procedure is debatable. The authors hypothesized that the choice of irrigation fluid might be a key factor affecting the outcomes of surgery. This multicenter randomized controlled trial aims to investigate whether intraoperative irrigation using artificial cerebrospinal fluid (ACF) followed by the placement of a subdural drain would yield superior results compared to the placement of a subdural drain alone for CSDH. METHODS: The study will be conducted across 19 neurosurgical departments in Japan. The 1186 eligible patients will be randomly allocated to two groups: irrigation using ACF or not. In either group, a subdural drain is to be placed for at least 12 h postoperatively. Similar to what was done in previous studies, we set the proportion of patients that meet the criteria for ipsilateral reoperation at 7% in the irrigation group and 12% in the non-irrigation group. The primary endpoint is the proportion of patients who meet the criteria for ipsilateral reoperation within 6 months of surgery (clinical worsening of symptoms and increased hematoma on imaging compared with the postoperative state). The secondary endpoints are the proportion of reoperations within 6 months, the proportion being stratified by preoperative hematoma architecture by computed tomography (CT) scan, neurological symptoms, patient condition, mortality at 6 months, complications associated with surgery, length of hospital stay from surgery to discharge, and time of the surgical procedure. DISCUSSION: We present the study protocol for a multicenter randomized controlled trial to investigate our hypothesis that intraoperative irrigation with ACF reduces the recurrence proportion after the removal of chronic subdural hematomas compared with no irrigation. TRIAL REGISTRATION: ClinicalTrials.gov jRCT1041220124. Registered on January 13, 2023.

Staphylococcus aureus Penicillin-Binding Protein 2 Can Use Depsi-Lipid II Derived from Vancomycin-Resistant Strains for Cell Wall Synthesis.

Vancomycin-resistant Staphylococcus aureus (S. aureus) (VRSA) uses depsipeptide-containing modified cell-wall precursors for the biosynthesis of peptidoglycan. Transglycosylase is responsible for the polymerization of the peptidoglycan, and the penicillin-binding protein 2 (PBP2) plays a major role in the polymerization among several transglycosylases of wild-type S. aureus. However, it is unclear whether VRSA processes the depsipeptide-containing peptidoglycan precursor by using PBP2. Here, we describe the total synthesis of depsi-lipid I, a cell-wall precursor of VRSA. By using this chemistry, we prepared a depsi-lipid II analogue as substrate for a cell-free transglycosylation system. The reconstituted system revealed that the PBP2 of S. aureus is able to process a depsi-lipid II intermediate as efficiently as its normal substrate. Moreover, the system was successfully used to demonstrate the difference in the mode of action of the two antibiotics moenomycin and vancomycin.

Cerebral hemorrhage and cerebral infarction in 30 cases of adult moyamoya disease: comparison between conservative therapy and superficial temporal artery-middle cerebral artery anastomosis.

To clarify the effect of surgery on the prevention cerebral hemorrhage in adult moyamoya disease, we compared postoperative courses between superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and conservative therapy. The study subjects were 30 adults with moyamoya disease. Unilateral STA-MCA anastomosis was conducted in 7 of these 30 cases, and bilateral STA-MCA anastomosis was conducted in 8 of these 30 cases. Therefore, anastomosis was performed in a total of 23 sides. The postoperative clinical course was observed for more than 5 years after the STA-MCA anastomosis. Cerebral hemorrhage occurred after operation in 2 sides (8.7%) among the 23 sides that received STA-MCA anastomosis. On the contrary, hemorrhage occurred during conservative therapy in 5 sides (13.5%) among 37 non-operation sides (no significance in chi2 test). Cerebral infarction occurred in 3 sides (13%) among 23 sides treated with STA-MCA anastomosis. However, the infarction occurred in 2 sides (5.4%) among the 37 non-operation sides (no significance in chi2 test). Cerebral hemorrhage tended to occur less frequently after STA-MCA anastomosis, and bypass surgery was suggested to have some beneficial effect in preventing cerebral hemorrhage in adult moyamoya disease. However, it was revealed that STA-MCA anastomosis exacerbated the brain ischemia. Therefore, strict management is mandatory in the perioperative period.

Atherothrombotic lesion of the middle cerebral artery: report of 21 cases with stenotic and obstructive lesions.

This was a retrospective analysis of 12 consecutive cases of middle cerebral artery stenosis and 9 consecutive cases of middle cerebral artery occlusion that presented to our hospital with acute cerebral ischemia. The degree and area of the cerebral infarctions were assessed with the Alberta Stroke Program Early CT Score (ASPECTS) and ASPECTS-DWI (APSECTS with assessment of white matter lesion using diffusion-weighted image). As for cerebral infarctions in the region of the perforating artery, lesions that were more than 20 mm long in the caudal-cranial direction were diagnosed as branch atheromatous disease (BAD). Activities of daily living (ADL) were poorer in the cases with lower ASPECTS and ASPECTS-DWI. ADL tended to be worse in cases with BAD than in those without. The prognosis was significantly poorer in the group with ASPECTS< or =7 points. ASPECTS tended to be lower in cases with BAD than in those without. ADL, ASPECTS and the presence of BAD were not significantly different between the stenosis and obstruction groups. In summary, the neurological prognosis was dependent on the extent of the cerebral infarction and was related to BAD to some extent. These findings will be important when considering medical treatment at the outpatient clinic setting.

[Subarachnoid hemorrhage caused by dissection of the basilar artery: a case report].

We report a case of subarachnoid hemorrhage, which was caused by dissection of the basilar artery during treatment for diabetes mellitus. The patient was a 60-year-old male who consulted our hospital complaining of sudden-onset of a severe headache. Head CT scan showed subarachnoid hemorrhage around the basilar artery, but 3D-CT angiography revealed no abnormality. The basilar artery was shown to be normal during cerebral angiography on Day 1. However, in retrospect pseudolumen of the basilar artery was suspected in the proximal portion of the branching point of the anterior inferior cerebellar artery. During a second cerebral angiography on Day 17, blood pressure elevated to 185/83mmHg and 30 minutes later this patient's consciousness deteriorated to 10 points of the GCS(E4, V2, M4). The double lumen in the basilar artery was identified around the branching point of the anterior inferior cerebellar artery. Head MRI on the same day showed intramural hemorrhage of the basilar artery as a high intensity lesion. Head MRI on Day 18 revealed multiple cerebellar infarctions in the region of the bilateral anterior inferior cerebellar arteries. His consciousness recovered to almost normal by reducing the blood pressure. Transient gait disturbance also recovered thereafter. Head MRI on Day 90 indicated disappearance of the intramural hemorrhage in the basilar artery. It was important to reduce the blood pressure to prevent recurrence of the arterial dissection.

[Factors which affect the neurological condition in subarachnoid hemorrhage].

The factors which were related to the neurological condition were analyzed in 233 cases of subarachnoid hemorrhage. Bivariate analysis and multiple(binomial)logistic regression analysis were performed as for Hunt & Kosnik grade, modified Rankin Scale at discharge and modified Rankin Scale in the out-patient department to detect the factors which were related to the neurological condition. Hematoma-filled intraventricular hemorrhage, intracerebral hemorrhage with midline shift, acute subdural hematoma and aneurysm of the vertebrobasilar system were the representative factors which caused poor neurological condition. Hunt & Kosnik grade was poor when rebleeding occurred or hematoma was formed in the sylvian fissure. Hunt & Kosnik grade and modified Rankin Scale at discharge tended to be poor in the cases with acute hydrocephalus. The elevation of intracranial pressure was the major factor in neurological deterioration.

[A case with Stanford type A acute aortic dissection that presented with consciousness disturbance and hemiparesis].

The patient was a 63-year-old female who had a past history of hypertension. She suddenly complained of agonizing pain and became comatose soon thereafter. Upon admission, she was in a state of shock, with upper airway obstruction and a coma. The pupils were dilated on both sides. The laboratory data showed that D-dimer was >80µg/mL. Brain CT scan and diffusion weighted MRI of the brain showed no abnormality. On brain 2D-CT angiography, the visualization of the right internal carotid artery and the right vertebral artery was poor. She eventually was able to nod her head in response to verbal commands, but her left extremities were completely hemiplegic. Cerebral angiography showed occlusion of the right vertebral artery at the branching point from the brachiocephalic artery, and was visualized in a retrograde fashion through the left vertebral artery. The brachiocephalic artery was severely stenotic in aortography. During angiography, she became able to speak and complained of back pain. Chest CT just after angiography showed a dissection in the aortic arch. Therefore, she was directed to the cardiovascular surgeon for immediate consultation. During the operation, the aortic dissection was revealed to be Stanford type A. Laceration of the intima was found in the ascending aorta and cardiac tamponade was also found. Total arch replacement was performed. The pathological examination showed that the arterial dissection occurred in the layer of elastic fiber, and the minimum arterial thickness of the medial layer was 0.2mm. The patient improved after the operation and her neurological deficits disappeared completely 13 days after operation. Brain and spinal MRI 15 days after the operation showed no abnormality.

Elucidation of the active conformation of vancomycin dimers with antibacterial activity against vancomycin-resistant bacteria.

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains.