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Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure–activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL–carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models. The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.

With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.

The European Lead Factory combines assets and experience from major pharma with innovation and agility of academia and SMEs in a collaborative platform to expand access to high-throughput screening. With many successes heading towards the clinic, the organization is broadening its approach to screening and partnering.The European Lead Factory combines assets and experience from major pharma with innovation and agility of academia and SMEs in a collaborative platform to expand access to high-throughput screening. With many successes heading towards the clinic, the organization is broadening its approach to screening and partnering.

Hepatitis C virus (HCV) has infected millions of people worldwide and emerged as a global health crisis. This review reports approaches currently being taken to combat the virus. Viral targets have received the most attention, particularly the NS3 serine protease where potent inhibitors have been described. Crystal structures of key replicative enzymes, NS3 protease, NS3 helicase, NS5B polymerase and now full-length NS3 protease-helicase, are available. More recently, targeting the host system has become of interest, particularly inhibitors of inosine monophosphate dehydrogenase. Research aimed at novel treatments for HCV disease is gathering pace and very recent developments in cell-based assay systems can only hasten the discovery of improved therapies.

A principal goal of treating patients with coronary artery disease (CAD) is to minimize angina and optimize quality of life. For this, physicians must accurately assess presence and frequency of patients’ angina. The accuracy with which cardiologists estimate their patients’ angina in contemporary, busy outpatient clinics across the United States (US) is unknown. We enrolled patients with CAD across 25 US cardiology outpatient practices. Patients completed the Seattle Angina Questionnaire before their visit, which assessed their angina and quality of life over the prior 4 weeks. The Seattle Angina Questionnaire angina frequency domain categorized patients’ angina as none, daily/weekly, or monthly. After the visit, cardiologists estimated the frequency of their patients’ angina using the same categories. Kappa statistic helped to assess agreement between patient-reported and cardiologist-estimated angina. Among 1,257 outpatients with CAD, 67% reported no angina, 25% reported monthly angina, and 8% reported daily/weekly angina. When patients reported no angina, cardiologists accurately estimated this 93% of the time, but when patients reported monthly or daily/weekly angina symptoms, cardiologists agreed 17% and 69% of the time, respectively. Among patients with daily/weekly angina, 26% were noted as having no angina by their physicians. Agreement between patients’ and cardiologists’ reports (assessed by the kappa statistic) was 0.48 (95% CI 0.44-0.53), indicating moderate agreement. Among outpatients with stable CAD, there is substantial discordance between patient-reported and cardiologist-estimated burden of angina. Inclusion of patient-reported health status measures in routine clinical care may support better recognition of patients’ symptoms by physicians.

The prevalence of radial access for transradial catheterization remains low in the United States, occurring in only 28% of cases in the National Cardiovascular Data Registry (NCDR) CathPCI. It is unknown whether the low adoption rate has been influenced by patient characteristics or is more operator dependent. In a 10-center study, we compared clinical and demographic characteristics among 323 radial and 1,506 femoral access percutaneous coronary intervention (PCIs) performed by 65 interventionists capable of radial PCI. We created a hierarchical logistic regression model to identify operator and patient characteristics associated with radial PCI and the median rate ratio to quantify the variation across operators. A subset was interviewed to assess health literacy and preferences in shared medical decision making. Radial access was used in 17.7% of patients. Patient factors associated with lower rate of radial PCI were previous PCI (33.4% vs 41.4%, p = 0.008), history of coronary artery bypass graft (8.4% vs 23.0%, p <0.001), and chronic total occlusion PCI (10.2% vs 17.9%, p <0.001). Operator characteristics associated with lower rate of radial PCI are being older, being longer in practice, lower number of publications, and Southern practice location. The range of radial use across operators was 1% to 99% and the median rate ratio was 1.97. Patients with radial access had lower health literacy, as assessed by the Rapid Estimate of Adult Literacy in Medicine Revised (REALM) score (6.6 ± 2.6 vs 7.1 ± 2.0, p = 0.03) but did not differ in their preferences for shared decision making. In conclusion, our study demonstrates a high degree of variability of radial access for PCI among different operators, with few differences in patient characteristics, suggesting that improvement efforts should focus on operators.

While the process of informed consent is designed to transfer knowledge of the risks and benefits of treatment and to engage patients in shared medical decision-making, this is poorly done in routine clinical care. We assessed the impact of a novel informed consent form for percutaneous coronary intervention (PCI) that is more simply written, includes images of the procedure, and embeds individualized estimates of outcomes on multiple domains of successful informed consent and shared decision-making. We interviewed 590 PCI patients receiving traditional consent documents and 527 patients receiving novel ePRISM consents at 9 US centers and compared patients’ perceptions, knowledge transfer, and engagement in medical decision-making. Heterogeneity across sites was assessed and adjusted for using hierarchical models. Site-adjusted analyses revealed more frequent review (72% for ePRISM vs 45% for original consents) and better understanding of the ePRISM consents (ORs=1.8-3.0, depending upon the outcome) with marked heterogeneity across sites (median relative difference [MRD] in the ORs of ePRISM’s effect =2-3.2). Patients receiving ePRISM consents better understood the purposes and risks of the procedure (ORs=1.9-3.9, MRDs=1.1-6.2), engaged more in shared decision-making (proportional OR=2.1 [95% CI=1.02-4.4], MRD=2.2) and discussed stent options with their physicians (58% vs. 31%; site-adjusted odds ratio=2.7 [95% CI=1.2, 6.3], MRD=2.6) more often. A personalized consent document improved the process of informed consent and shared decision-making. Marked heterogeneity across hospitals highlights that consent documents are but one aspect of engaging patients in understanding and participating in treatment.

Patients with diabetes mellitus (DM) experience higher rates of in-stent restenosis and greater benefit from drug-eluting stents implant at the time of percutaneous coronary intervention (PCI), necessitating prolonged dual anti-platelet therapy (DAPT). While DAPT reduces risk of ischemic events post-PCI, it also increases risk of bleeding. Whether bleeding rates differ among patients with and without DM, receiving long-term DAPT is unknown. Among patients who underwent PCI and were maintained on DAPT for 1 year in a multicenter US registry, we assessed patient-reported bleeding over one year following PCI in patients with and without DM. Multivariable, hierarchical Poisson regression was used to evaluate the association of DM with bleeding during follow-up. Among 2334 PCI patients from 10 US hospitals (mean age 64, 54% ACS), 32.6% had DM. In unadjusted analyses, patients with DM had fewer bleeding events over the year following PCI (DM vs no DM: BARC = 1: 78.0% vs 87.7%, P < .001; BARC ≥2: 4.3% vs 5.3%, P = .33). Following adjustment, patients with (vs without DM) had a lower risk of BARC ≥1 bleeding during follow-up (relative risk [RR] 0.89, 95% CI 0.83–0.96). This decreased bleeding risk persisted after removing bruising from the endpoint definition. In a real-world PCI registry, patients with DM experienced lower risk of bleeding risk on DAPT. As patients with DM also derive greater ischemic benefit from drug-eluting stents, which requires prolonged DAPT, our findings suggest that the balance between benefit and risk of this therapeutic approach may be even more favorable in patients with DM than previously considered.