Numerical fatigue damage models can help to save cost and time when studying fatigue damage in the copper metallization layers of power semiconductor devices. However, their predictive capabilities ...strongly depend on the parameters associated with these models. This paper presents a strategy for calibrating parameters of a numerical fatigue damage model using experimental results from thermomechanical fatigue experiments. Fatigue damage is predicted by the Fatemi–Socie critical plane method in combination with a Coffin–Manson law. Experimentally, test devices are utilized which can reproduce loading conditions that approximate those occurring in real semiconductor devices. Damage is measured in form of visible surface cracks by the means of surface imagery. Experimental results from devices with pronounced lateral thermal gradients are used for calibrating the fatigue parameters of the Coffin–Manson law. Eventually, the model with the calibrated fatigue parameters is used to predict fatigue damage for a second experiment with different loading conditions. For all investigated test devices the numerical predictions are in good agreement with experimental results. The simulations show that significantly more damage occurs in regions with higher temperatures and that the surface topology has a strong influence on local fatigue damage.
•A novel concept for calibrating a numerical fatigue damage model is presented.•Thermomechanical loading conditions are considered during calibration.•Regions of high temperature experience high fatigue damage.•Small topological irregularities cause strong local effects.•Predictive capabilities of the calibrated model are demonstrated.
The success of hit-finding campaigns relies on many factors, including the quality and diversity of the set of compounds that is selected for screening. This paper presents a generalized workflow ...that guides compound selections from large compound archives with opportunities to bias the selections with available knowledge in order to improve hit quality while still effectively sampling the accessible chemical space. An optional flag in the workflow supports an explicit complement design function where diversity selections complement a given core set of compounds. Results from three project applications as well as a literature case study exemplify the effectiveness of the approach, which is available as a KNIME workflow named Biased Complement Diversity (BCD).
CUO246, a novel DNA gyrase/topoisomerase IV inhibitor, is active
against a broad range of Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens and retains activity against ...quinolone-resistant strains in circulation. The frequency of selection for single step mutants of wild-type S. aureus with reduced susceptibility to CUO246 was <4.64 × 10
at 4× and 8× MIC and remained low when using an isogenic QRDR mutant (<5.24 × 10
at 4× and 8× MIC). Biochemical assays indicated that CUO246 had potent inhibitory activity against both DNA gyrase (GyrAB) and topoisomerase IV (ParCE). Furthermore, CUO246 showed rapid bactericidal activity in time-kill assays and potent
efficacy against S. aureus in a neutropenic murine thigh infection model. These results suggest that CUO246 may be useful in treating infections by various causative agents of acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.
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Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative ...bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).
New aminoglycoside antibiotics Dozzo, Paola; Moser, Heinz E
Expert opinion on therapeutic patents
20, Številka:
10
Journal Article
Recenzirano
Nosocomial infections caused by multi-drug resistant (MDR) Gram-negative bacteria are on the increase, often with few or no therapeutic options for treatment. Historically, a successful approach to ...generate novel antibiotics has been the chemical modification of existing classes, addressing deficiencies such as resistance mechanisms, safety profile or pharmacokinetic parameters. Aminoglycosides (AGs) represent one of the five clinically-used classes (AGs, β-lactams, quinolones, tetracyclines and sulfonamides) with activity against Gram-negative bacteria.
A summary of the AG patent literature between the beginning of 2005 and February 2010 with the main focus on novel AG analogs with potential for therapeutic activity against MDR Gram-negative pathogens.
Overview of the patent literature in the aminoglycoside field during the past 5 years including an assessment of the therapeutic potential for the derivatives described.
A few companies and academic groups have recently reawakened the dormant field of AG antibiotics, successfully applying novel technologies. So far, this has yielded one clinical candidate, ACHN-490, currently undergoing a Phase II evaluation in complicated urinary tract infections.
As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have ...solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site—the E-site—found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252–14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of β-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site.
β3‐Octaarginine chains were attached to the functional groups NH and CO2H of the antibacterial fluoroquinolones ciprofloxacin (→1) and enrofloxacin (→2), respectively, in order to find out whether ...the activity increases by attachment of the polycationic, cell‐penetrating peptide (CPP) moiety. For comparison, simple amides, 3–5, of the two antimicrobial compounds and β3‐octaarginine amide (βR8) were included in the antibacterial susceptibility tests to clarify the impact of chemical modification on the microbiological activity of either scaffold (Table).
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