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There are limited therapeutic options for extensively drug-resistant tuberculosis. In this study from South Korea, linezolid was shown to have some activity in treating resistant tuberculosis; however, its use was associated with clinically significant toxicity. Linezolid (Zyvox, Pfizer) was approved in 2000 for drug-resistant, gram-positive bacterial infections. 1 A member of the oxazolidinone antibiotic class, linezolid inhibits protein synthesis by binding the 23S ribosomal RNA (rRNA) portion of the bacterial 50S ribosomal subunit. 2 In adults, linezolid is administered at a dose of 600 mg twice daily, with phase 3 and postmarketing trials showing an acceptable side-effect and adverse-event profile during the FDA-approved 28 days of therapy. 3 Data on longer-term use are limited, but serious neuropathies (e.g., peripheral and optic neuropathies), myelosuppression, and hyperlactatemia have been observed 4 , 5 and are considered to be related to the inhibition . . .

Long-acting antiretrovirals can address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and adherence. In two phase 3 trials, twice-yearly subcutaneous lenacapavir was safe and highly efficacious for PrEP in diverse populations. Furthering long-acting PrEP efforts, this study assessed the pharmacokinetics and safety of two once-yearly intramuscular lenacapavir formulations. This phase 1, open-label study in participants aged 18–55 years without HIV evaluated the pharmacokinetics, safety, and tolerability of two lenacapavir free acid formulations administered by ventrogluteal intramuscular injection as a single 5000 mg dose (formulation 1 with 5% w/w ethanol, formulation 2 with 10% w/w ethanol). Pharmacokinetic samples were collected at prespecified timepoints up to 56 weeks. Lenacapavir plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method and summarised with non-compartmental analysis. Pharmacokinetic parameters evaluated included the area under the concentration–time curve for the once-yearly dosing interval calculated from days 1 to 365 (AUCdays 1–365), peak plasma concentration, time to reach peak plasma concentration, and trough concentration (Ctrough). Plasma concentration data from phase 3 studies of twice-yearly subcutaneous lenacapavir (PURPOSE 1 and PURPOSE 2) were pooled for comparison with once-yearly intramuscular lenacapavir formulations. Safety and tolerability, including participant-reported pain scores, were assessed. 20 participants received lenacapavir formulation 1 and 20 received lenacapavir formulation 2. For estimation of pharmacokinetic parameters, sample size varied over time with at least 13 participants (formulation 1) and at least 19 participants (formulation 2) due to early discontinuations for reasons unrelated to the study drug. Following administration of intramuscular lenacapavir, concentrations increased rapidly, and median time to maximum concentration was 84·1 days (IQR 56·1–112·0) for formulation 1 and 69·9 days (55·3–105·5) for formulation 2. The highest median concentration of once-yearly intramuscular lenacapavir (247·0 ng/mL [IQR 184·0–346·0] for formulation 1, 336·0 ng/mL [233·5–474·3] for formulation 2) remained above the highest median twice-yearly subcutaneous lenacapavir concentration (67·3 ng/mL [46·8–91·4]). Median Ctrough at the end of 52 weeks for formulation 1 was 57·0 ng/mL (IQR 49·9–72·4) and for formulation 2 was 65·6 ng/mL (41·8–87·1), exceeding the median twice-yearly subcutaneous lenacapavir Ctrough of 23·4 ng/mL (15·7–34·3) at the end of 26 weeks. Median AUCdays 1–365 for formulation 1 was 1011·1 h*μg/mL (IQR 881·0–1490·2) and for formulation 2 was 1274·0 h*μg/mL (1177·3–1704·8). Adverse events were mostly grade 1 or 2. The most common was injection-site pain (16 [80%] participants given formulation 1, 15 [75%] given formulation 2), which was generally mild, resolved within 1 week, and was substantially reduced by pretreatment with ice. Following administration of once-yearly intramuscular lenacapavir, median plasma concentrations exceeded those associated with efficacy in phase 3 studies of twice-yearly subcutaneous lenacapavir for PrEP for at least 56 weeks. Both formulations were safe and well tolerated. These data show the potential for biomedical HIV prevention with a once-yearly dosing interval. Gilead Sciences.

The present study demonstrated the design and synthesis of sulfonamide-1,2,3-triazole-acetamide derivatives 11a-o and screening against urease in vitro and in silico. These compounds were designed based on reported potent urease inhibitors and optimized structurally based on substituents on acetamide moiety. In vitro studies showed that all the new compounds 11a-o (IC 50 values = 0.12–4.53 µM) were more potent than stand inhibitor thiourea (IC 50 value = 23.76 µM). In this regard, the most potent compounds were N-phenylacetamide derivatives 11b , 11f , and 11 h with 2-methyl, 4-methoxy, and 2-fluoro substituents, respectively. In this regard, the most potent compound 11b was 198-folds more potent than thiourea against urease. In silico studies demonstrated that this compound with the binding energy less than thiourea attached to the urease’s active site. Druglikeness, pharmacokinetics, and toxicity of compound 11b and thiourea were predicted by two credible online servers. These in silico studies showed that, in terms of druglikeness and pharmacokinetics, compound 11b was almost similar to thiourea while in term of toxicity, compound 11b was better than thiourea.

Background. Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. Methods. This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare—associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. Results. Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). Conclusions. For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

The persistence of H5N1 avian influenza viruses in many Asian countries and their ability to cause fatal infections in humans have raised serious concerns about a global flu pandemic. Here we report the isolation of an H5N1 virus from a Vietnamese girl that is resistant to the drug oseltamivir, which is an inhibitor of the viral enzyme neuraminidase and is currently used for protection against and treatment of influenza. Further investigation is necessary to determine the prevalence of oseltamivir-resistant H5N1 viruses among patients treated with this drug.

Klebsiella pneumoniae causes a wide range of community and nosocomial infections. The high capacity of this pathogen to acquire resistance drugs makes it necessary to develop therapeutic alternatives, discovering new antibacterial molecules. Acetamides are molecules that have several biological activities. However, there are no reports on the activity of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide. Based on this, this study aimed to investigate the in vitro antibacterial activity of this molecule on K. pneumoniae, evaluating whether the presence of the chloro atom improves this effect. Then, analyzing its antibacterial action more thoroughly, as well as its cytotoxic and pharmacokinetic profile, in order to contribute to future studies for the viability of a new antibacterial drug. It was shown that the substance has good potential against K. pneumoniae and the chloro atom is responsible for improving this activity, stabilizing the molecule in the target enzyme at the site. The substance possibly acts on penicillin-binding protein, promoting cell lysis. The analysis of cytotoxicity and mutagenicity shows favorable results for future in vivo toxicological tests to be carried out, with the aim of investigating the potential of this molecule. In addition, the substance showed an excellent pharmacokinetic profile, indicating good parameters for oral use.

Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN–BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein–protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.

Among over 1100 patients with pulmonary arterial hypertension who received selexipag, an oral selective IP prostacyclin-receptor agonist, or placebo, the risk of the composite end point of death or complication was lower with selexipag than with placebo at 1.3 years of follow-up. Pulmonary arterial hypertension is a severe disease with a poor prognosis despite available treatment options. 1 Current recommendations support the use of a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. 2 , 3 Despite the benefits of intravenous prostacyclin therapy, 2 , 4 many patients with pulmonary arterial hypertension die without ever receiving this treatment. 5 , 6 The burden and risks related to the administration of prostacyclin therapy are probably contributing factors. 7 Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. 8 – 11 In a placebo-controlled, phase 2 trial involving patients who were already receiving treatment for pulmonary . . .

The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases. Proteins are often described as life's ‘workhorse’ molecules, and cells must be able to build new proteins to stay alive. This ability is also vital for storing new memories. A protein called eIF2 carries out a critical step in the process that cells use to make proteins; and a decrease in the activity of eIF2 has been linked with memory loss in diseases such as Parkinson's and Alzheimer's disease. When a cell experiences stressful conditions—such as virus infection or starvation—it triggers the ‘integrated stress response’. This response helps the cell conserve its resources and take corrective steps to restore its normal working conditions. As part of the integrated stress response, an enzyme adds a phosphate group onto eIF2. The ‘phosphorylated’ eIF2 blocks protein production, which causes the cell to make fewer proteins. In 2013, researchers revealed that a small drug-like molecule, called ISRIB, could prevent this decline in protein production following eIF2 phosphorylation; and when ISRIB was administered to mice and rats, it enhanced their long-term memories. However, this early work did not identify the molecule that is targeted by ISRIB. Now Sidrauski, Tsai et al.—including many of researchers involved in the 2013 work—have used a combination of techniques including genetics, chemistry and biochemistry to reveal the target of ISRIB. The experiments show that ISRIB's molecular target is a protein complex called eIF2B. Artificially reducing the production of eIF2B made cells resistant to the effects of ISRIB. The eIF2B protein normally works to activate eIF2; Sidrauski, Tsai et al. observed that ISRIB boosts the activity of eIF2B and renders it insensitive to blockage by phosphorylated eIF2. This in turn increases protein production in the cell. But how does ISRIB activate eIF2B? It was known that two copies of eIF2B can bind to each other; and Sidrauski, Tsai et al. found that ISRIB acts by stabilizing these larger protein complexes that are more active and less sensitive to inhibition by phosphorylated eIF2. Finally, in further experiments, new versions of ISRIB were synthesized that are ten-times as active as the original molecule inside cells. Importantly, the discovery that eIF2B is the molecular target for ISRIB has recently been independently validated by other researchers, and it looks promising that this discovery will guide future efforts to develop clinically useful drugs to treat memory disorders.

The tubulin polymerization and Src kinase inhibitor tirbanibulin was superior to placebo ointment in clearing actinic keratoses on the face and scalp at 2 months. As is typical of the disorder, lesions recurred in 47% of patients at 1 year. Adverse events were related to local irritation.