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Background The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. Objectives A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). Methods Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. Results No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean T max range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean T max 3.87 h), a lower C max (−17.7%) and increased AUC0– t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both C max and AUC0–tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0–tau) compared with C max (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. Conclusions Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food. [ABSTRACT FROM AUTHOR]

Background: Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE.Objectives: To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates.Methods: Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017-19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin's mode of action and resistance mechanisms.Results: Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore-drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10-9 at rifabutin concentrations at or above 2 mg/L.Conclusions: This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver. [ABSTRACT FROM AUTHOR]