Basic and applied studies on multiple aminoglycoside antibiotic (AG) resistance in actionmycetes were carried out. AG producers exhibited individual AG resistance profiles representing substrate specificities of AG-modifying enzymes and/or AG-resistance specificities of ribosomes as self-resistance factors. In some strains, however, additional factors were found to be involved. They included AG acetyltransferases such as the activated cryptic AAC(3) in streptomycin-producing Streptomyces griseus SS-1198PR and an AAC(2’) in kasugamycin-producing S. kasugaensis MB273. In the former we demonstrated the gene activation due to one base substitution of T for C at the -10 promoter region and the modification at the novel site (3”-NH₂) of arbekacin (ABK) and amikacin (AMK). The latter was characterized by its novel capability of acetylating ABK and astromicin (ASTM) at 2’-NH₂. An AAC(6’) regarded as an nonself-resistance factor in an ABK resistant actinomycete strain #8 was characterized by its capability of acetylating semisynthetic AGs (ABK, AMK, isepamicin and netilmicin) and ASTM at 6’-NH₂.
As an application study of multiple AG resistance factors, these AACs were used for predictive investigations of the possible emergence of AAC-dependent resistance to ABK known to be refractory to the AACs of clinical origin. Consequently, we discovered the unexpected antibiotic activity of ABK acetylation products by AAC(3), AAC(2’) and AAC(6’) indicating little possibility of the emergence of AAC-dependent ABK resistance.