Three different colonial variants of Mycobacterium avium complex were studied for their susceptibilities to capric, lauric, oleic, and linolenic acids. Smooth T variants with transparent and irregularly shaped colonies were much more resistant to all the fatty acids than were the smooth D variants with opaque and dome-shaped colonies. Rough variants with granular and irregularly shaped colonies showed nearly the same susceptibility to the fatty acids as did the smooth T variants.Mycobacterium avium complex has three known types of colonial variants: the "smooth T" variant, with a transparent and irregularly shaped colony; the "smooth D" variant, with an opaque and dome-shaped colony; and the "rough" variant, with a granular and irregularly shaped colony (9, 18). These colonial variants differ in susceptibility to various antimicrobial agents such as streptomycin, kanamycin, rifampin, and erythromycin (21), as well as paromomycin, viomycin, and mitomycin (10) and other inhibitory agents such as malachite green and methyl violet (21). Smooth T variants show a much higher resistance to these agents than do the smooth D variants (7,21). In recent work, we found that smooth T variants were also much more resistant to rifabutine, a newly developed derivative of rifamycin-S (17), to some new quinolones such as ofloxacin and ciprofloxacin, and to cefoxitin than were the smooth D variants. The rough variants showed an intermediate susceptibility (H. Saito, K. Sato, and H. Tomioka, submitted for publication).With regard to the mechanism for this difference in susceptibility to antimicrobial agents among these colonial variants of M. avium complex, Rastogi et al. (15) proposed the important role of the outer, regularly structured layer in smooth T variants, which is lacking in the smooth D variants. They suggested that the polysaccharide outer layer may be related to an impaired permeability in smooth T variants. Indeed, Tween 80, which seriously damages the outer layer (S. Naik, personal communication), markedly increases the susceptibility of M. avium complex to antimicrobial agents (3,11). On the other hand, both the smooth T and smooth D variants showed similar susceptibility to isoniazid, ethambutol, and eosin Y (10, 21). It is also known that Tween 80 conversely decreases the susceptibility of M. avium complex to isoniazid (11). Therefore, the mechanisms related to this phenomenon are more complicated and are not simply based on the polysaccharide outer layer on smooth T variants. In the present study, we compared the susceptibility of the three colonial variants of various strains of M. avium complex to long-chain fatty acids with a strong hydrophobicity, since this seems to be a possible approach for better understanding of the mechanisms of drug resistance of M. avium complex.The three colonial variants of M. avium complex strains N-235, N-260, N-275, and N-279 106 to 4 x 107), was incubated with reciprocal shaking (100 cycles/min) at 37°C for 1 h, and then 1 ml of the mixture was diluted with 3 ml of cold phospha...