1289. Pravibismane is a Potent, Broad Spectrum Anti-Infective Small Molecule that Rapidly Disrupts Bacterial Bioenergetics and Halts Bacterial Growth

Abstract

Meiji Seika Pharma Co., Ltd. Session: P-58. Novel Agents Background. A single administration of nacubactam (NAC) with concomitant β-lactams in Japanese healthy subjects was conducted to assess pharmacokinetics (PK), safety, and tolerability of NAC in coadministration with cefepime (FEP), aztreonam (ATM), meropenem (MEM), or piperacillin (PIP). Methods. The administration period included Period I, Period II, and Period III where NAC alone, concomitant drug alone, NAC and concomitant drug were administered by 1hour-IV infusion in each period. The dose of each drug tested was 2 g of NAC, FEP, ATM, MEM and 4 g of PIP and 8 subjects were administered in each cohort (32 subjects in total). Results. Plasma NAC concentrations and NAC urinary excretion rate after coad-ministration with each concomitant drug were similar to those of administration of NAC alone. The PK parameter of NAC showed the similar value both after administration of NAC alone and after concomitant administration with each concomitant drug. Based on these findings, it was confirmed that coadministration of NAC with FEP, ATM, MEM or PIP did not affect the PK of NAC. Plasma concentrations and urinary excretion rate of FEP, ATM, MEM or PIP after coadministration of each concomitant drug with NAC were similar to those of administration of each concomitant drug alone. The PK parameter of each β-lactam tested showed the similar value both after administration of β-lactam alone and after concomitant administration with NAC. Based on these finding, it was confirmed that coadministration of each concomitant drug with NAC did not affect the PK of FEP, ATM, MEM and PIP. As for the safety, there was no serious adverse event, all of TEAEs reported were mild in severity and judged to be "not related". Conclusion. It was confirmed that single coadministration of NAC with FEP, ATM, MEM, or PIP did not affect the both PKs of NAC and β-lactams, and was safe and well-tolerated in Japanese healthy subjects. Session: P-58. Novel Agents Background. SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzim-idazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-inhuman single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmaco-kinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods. This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results. A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma C max and AUC 0-24 , respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t 1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was similar at Days 7 and 14. Conclusion. Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Session: P-58. Novel Agents Background. The rise in resistance to existing antimicrobials has prompted a need for the development of novel antibiotics. Microbion has identified a novel compound , pravibismane, with potent broad spectrum anti-infective and anti-biofilm activity. Methods. Here we used a variety of assays, including Bacterial Cytological Profiling (BCP), to analyze pravibismane in E.coli to gain insight into its likely mechanism of action (MOA). The BCP profile of pravibismane suggested it rapidly shut down cell growth, potentially by turning off cellular gene or protein expression. This was confirmed using a plasmid based GFP induction assay in E.coli tolC that showed pravibismane strongly reduced expression of GFP. The kinetics, reversibility and MOA of pravibismane was further characterized by using time-lapse microscopy, wash out experiments and measurements of both membrane potential and relative intracellular ATP levels. Results. We found that pravibismane acts rapidly (within 30 mins) to completely halt cell growth rather than causing immediate cell lysis such as that observed with non-specific cell damaging agents bleach or detergent. Inhibitor wash out experiments in which cells were exposed to pravibismane for 2 hours, washed to remove