Physicochemical solubility of and biological sensitivity to long-chain alcohols determine the cutoff chain length in biological activity.

The cutoff phenomenon associated with the effectiveness of long-chain alcohols in the induction of anesthesia is also observed for various antimicrobial activities, although the mechanism has remained unknown for over eight decades. The minimum inhibitory concentrations at 25 degrees C for budding yeast growth exponentially decreased with increasing chain length of n-alcohols (C-2-C-12), whereas alcohols >= C-13 lost the inhibitory effect. Thus, growth inhibition by n-alcohols obeys the Meyer-Overton correlation up to C-12 and exhibits a cutoff phenomenon. The densities of n-alcohols are low, and the melting point and hydrophobicity increase with chain length. C-13 and C-14 inhibited yeast growth at 39.8 degrees C, above their melting points. Alcohols <= C-14 inhibited thermophilic bacterial growth at 50 degrees C, whereas C-16 inhibited it at 67.5 degrees C, above their melting points. Thus, the high melting points of long-chain alcohols contribute to the cutoff phenomenon. C-14 did not effectively inhibit yeast growth in a static culture at 39.8 degrees C, in contrast to a shaking culture, in which the low density-dependent concentration gradient was eliminated. The duration of the transient growth inhibition of yeast by C-12 was prolonged by sonication, which prevented hydrophobic aggregation. Therefore, a nonuniform distribution owing to low density and high hydrophobicity contributes to the cutoff. C-14 inhibited the growth at 25 degrees C of the pdr1,3,5 mutant, defective in multidrug efflux pumps, whereas C-12 did not inhibit the growth of yeast overexpressing PDR5, indicating that the sensitivity to long-chain alcohols contributed to the cutoff. A balance between the physicochemical solubility of and the biological sensitivity to long-chain alcohols determines the cutoff chain length.