Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598.

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development.

VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report a first-in-human study to evaluate safety and pharmacokinetics after an oral dose of VT-1598.

Tryptoline-based benzothiazoles re-sensitize MRSA to ß-lactam antibiotics.

Resistance-modifying agents (RMAs) offer a promising solution to combat bacterial antibiotic resistance. Here we report the discovery and structure-activity relationships of a new class of RMAs with a novel tryptoline-based benzothiazole scaffold. Our most potent compound in this series (4ad) re-sensitizes multiple MRSA strains to cephalosporins at low concentrations (2 µg/mL) and has low mammalian cytotoxicity with a half growth inhibitory concentration (GI50) > 100 µg/mL in human cervical carcinoma (HeLa) cells. In addition, the same core scaffold with different substitutions also gives good antibacterial activity against MRSA.

Development and comparison of immunologic assays to detect primary RSV infections in infants.

Effective respiratory syncytial virus (RSV) vaccines have been developed and licensed for elderly adults and pregnant women but not yet for infants and young children. The RSV immune state of the young child, i.e., previously RSV infected or not, is important to the conduct and interpretation of epidemiology studies and vaccine clinical trials. To address the need for sensitive assays to detect immunologic evidence of past infection, we developed, characterized, and evaluated 7 assays including 4 IgG antibody enzyme immunoassays (EIAs), two neutralizing antibody assays, and an IFN-γ EliSpot (EliSpot) assay. The four IgG EIAs used a subgroup A plus subgroup B RSV-infected Hep-2 cell lysate antigen (Lysate), an expressed RSV F protein antigen (F), an expressed subgroup A G protein antigen (Ga), or an expressed subgroup B G protein (Gb) antigen. The two neutralizing antibody assays used either a subgroup A or a subgroup B RSV strain. The EliSpot assay used a sucrose cushion purified combination of subgroup A and subgroup B infected cell lysate. All seven assays had acceptable repeatability, signal against control antigen, lower limit of detection, and, for the antibody assays, effect of red cell lysis, lipemia and anticoagulation of sample on results. In 44 sera collected from children >6 months after an RSV positive illness, the lysate, F, Ga and Gb IgG EIAs, and the subgroup A and B neutralizing antibody assays, and the EliSpot assays were positive in 100%, 100%, 86%, 95%, 43%, and 57%, respectively. The Lysate and F EIAs were most sensitive for detecting RSV antibody in young children with a documented RSV infection. Unexpectedly, the EliSpot assay was positive in 9/15 (60%) of PBMC specimens from infants not exposed to an RSV season, possibly from maternal microchimerism. The Lysate and F EIAs provide good options to reliably detect RSV antibodies in young children for epidemiologic studies and vaccine trials.