PT  - JOURNAL ARTICLE
AU  - Atsushi Matsumoto
AU  - Yukifumi Uesono
TI  - Physicochemical solubility of and biological sensitivity to long-chain alcohols determine the cutoff chain length in biological activity
AID  - 10.1124/mol.118.112656
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.112656
4099  - http://molpharm.aspetjournals.org/content/early/2018/10/05/mol.118.112656.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/10/05/mol.118.112656.full
AB  - The cutoff phenomenon that long-chain alcohols are unable to induce anesthesia is observed for various antimicrobial activities, although its mechanism has remained unknown for over eight decades. The minimum inhibitory concentrations at 25°C for budding yeast growth exponentially decreased with increasing chain length of the n-alcohols (C1 - C12), whereas alcohols (≥C13) lost the inhibitory effect. Thus, the growth inhibition by n-alcohols obeys the Meyer - Overton correlation up to C12 and exhibits a cutoff phenomenon. The densities of n-alcohols are low, and the melting point and hydrophobicity increase with chain length. C13 and C14 inhibited yeast growth at 39.8°C, above their melting points. The alcohols (≤C14) inhibited thermophilic bacterial growth at 50°C, whereas C16 inhibited it at 67.5°C, above their melting points. Thus, high melting points of long-chain alcohols contribute to the cutoff phenomenon. C14 did not effectively inhibit yeast growth in a static culture at 39.8°C, in contrast to the shaking culture, eliminating the low density-dependent concentration gradient. The duration of the transient growth inhibition of yeast by C12 was prolonged by sonication, preventing hydrophobic aggregation. Therefore, a nonuniform distribution due to low density and high hydrophobicity contributes to the cutoff. C14 inhibited the growth at 25°C of the pdr1,3,5 mutant, defective in multidrug efflux pumps, whereas C12 did not inhibit the growth of yeast overexpressing PDR5, indicating that the sensitivity to long-chain alcohols contributes to the cutoff. A balance between the physicochemical solubility of and the biological sensitivity to long-chain alcohols determines the cutoff chain length.