In this work, a novel mechanistic model of hop inhibition beyond the proton ionophore action toward (beer spoiling) bacteria was developed. Investigations were performed with model systems using cyclic voltammetry for the determination of redox processes/conditions in connection with growth challenges with hop-sensitive and -resistant Lactobacillus brevis strains in the presence of oxidants. Cyclic voltammetry identified a transmembrane redox reaction of hop compounds at low pH (common in beer) and in the presence of manganese (present in millimolar levels in lactic acid bacteria). The antibacterial action of hop compounds could be extended from the described proton ionophore activity, lowering the intracellular pH, to pronounced redox reactivity, causing cellular oxidative damage. Accordingly, a correlation between the resistance of L. brevis strains to a sole oxidant to their resistance to hop could not be expected and was not detected. However, in connection with our recent study concerning hop ionophore properties and the resistance of hop-sensitive and -tolerant L. brevis strains toward proton ionophores (J. Behr and R. F. Vogel, J. Agric. Food Chem. 57:6074-6081, 2009), we suggest that both ionophore and oxidant resistance are required for survival under hop stress conditions and confirmed this correlation according to the novel mechanistic model. In consequence, the expression of several published hop resistance mechanisms involved in manganese binding/transport and intracellular redox balance, as well as that of proteins involved in oxidative stress under "highly reducing" conditions (cf. anaerobic cultivation and "antioxidative" hop compounds in the growth medium), is now comprehensible. Accordingly, hop resistance as a multifactorial dynamic property at least implies distinct resistance levels against two different mechanisms of hop inhibition, namely, proton ionophore-induced and oxidative stress-induced mechanisms. Beyond this specific model of hop inhibition, these investigations provide general insight on the role of electrophysiology and ion homeostasis in bacterial stress responses to membrane-active drugs.The inflorescences of the hop plant Humulus lupulus are traditionally used for beer brewing, due to the pleasant bitterness of hop compounds in beer and their additional inhibitory effect on bacteria. These antibiotic and bacteriostatic properties of hops comprise several inhibitory mechanisms. The described effects of hop compounds on bacteria are permeability changes in the bacterial cell wall (30), leakage of the cytoplasmic membrane and a subsequent inhibition of respiration, and protein, DNA, and RNA synthesis (42), as well as changes in leucine uptake and proton ionophore activity (33). In a recent study (5), we characterized the latter ionophore properties of hop compounds in a cell-free model system via bilayer lipid membrane (BLM) techniques in connection with growth challenges of hop-sensitive and -resistant Lactobacillus brevis strains. The antibacterial action of iso-␣-acids as prot...