A phase III randomized controlled non-inferiority trial to study the efficacy and safety of imipenem/cilastatin/relebactam (IMI/REL) versus piperacillin/tazobactam (PIP/TAZ) in patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).

Objectives: Imipenem/cilastatin/relebactam (IMI/REL) is a β-lactam/β-lactamase inhibitor combination effective against gram-negative pathogens. Efficacy and safety of IMI/REL were studied in critically ill adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).

Methods: In this phase III, double-blind, multinational, randomized trial (NCT03583333), adults with HABP/VABP were randomized 1:1 to receive intravenous IMI/REL (500 mg/250 mg) or piperacillin/tazobactam (PIP/TAZ; 4000 mg/500 mg) every 6 h for 7-14 days.

A phase 3, multicenter, randomized, double-blind, active-comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants (PNEU-PED).

Background: Pneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and additional serotypes 22F and 33F.

Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer.

Benzimidazole analogs as WTA biosynthesis inhibitors targeting methicillin resistant Staphylococcus aureus.

A series of benzimidazole analogs have been synthesized to improve the profile of the previous lead compounds tarocin B and 1. The syntheses, structure-activity relationships, and selected biochemical data of these analogs are described. The optimization efforts allowed the identification of 21, a fluoro-substituted benzimidazole, exhibiting potent TarO inhibitory activity and typical profile for a wall teichoic acid (WTA) biosynthesis inhibitor.

Discovery of potent wall teichoic acid early stage inhibitors.

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current β-lactam antibiotics and created an urgent need for novel treatment options. Using an S. aureus phenotypic screening strategy, we have identified small molecule early stage wall teichoic acid (WTA) pathway-specific inhibitors predicted to be chemically synergistic with β-lactams.

TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci.

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current β-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis.

Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis.

Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4.

AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines.

AKT is a key serine/threonine kinase in the PTEN/PI3K/AKT pathway(1) and activationof AKT is often observed in human cancers. To explore the role of AKT in cell survival in different tumor cells, we tested 20 human tumor cell lines for response to knockdown of AKT by small interference RNA (siRNA) and/or a kinase-dead mutant AKT. siRNA-mediated knockdown of all three AKT isoforms in tumor cell lines led to a reduction of phosphorylation of AKT substrates.

Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors.

We used gene expression profiling to probe differences in transcriptional output between 15 panels of colon tumor and matched normal colon tissues. This analysis revealed that GPR49, an orphan G Protein-Coupled Receptor (GPCR) is overexpressed in 66% (10/15) colon tumors compared with normal colon tissues. Subsequent analysis of an additional 39 sets of matched normal and tumor colon tissues by real-time quantitative reverse transcriptase confirmed the upregulation of this receptor.

Development of a fluorescence polarization bead-based coupled assay to target different activity/conformation states of a protein kinase.

Most of the protein kinase inhibitors being developed are directed toward the adenosine triphosphate (ATP) binding site that is highly conserved in many kinases. A major issue with these inhibitors is the specificity for a given kinase. Structure determination of several kinases has shown that protein kinases adopt distinct conformations in their inactive state, in contrast to their strikingly similar conformations in their active states.

Transforming growth factor-beta 2 is a transcriptional target for Akt/protein kinase B via forkhead transcription factor.

Tumors evade cell death by constitutively activating cell survival pathways and suppressing intrinsic death machinery. Activation of cell survival pathways leads to transcriptional repression of genes associated with cell death and activation of ones promoting anti-apoptosis. Akt/protein kinase B phosphorylates forkhead transcription factors and prevents their nuclear localization, leading to repression of genes involved in apoptosis, such as Fas ligand (FasL).