P37
Search for circumventors of arbekacin resistance in MRSA
Sunday, January 11, 2015
California Ballroom C and Santa Fe Room
An aminoglycoside antibiotic, arbekacin (ABK), is very useful for treating MRSA, but ABK-resistant MRSA are being found. ABK resistance is mainly caused by bacterial bifunctional aminoglycoside-modifying enzyme (AAC(6’)-Ie/APH(2”)-Ia), which phosphorylates and acetylates ABK. Therefore, any inhibitor of this enzyme may circumvent ABK resistance, and could be used as a combination drug, together with ABK, against ABK-resistant MRSA. We devised a simple method to screen for inhibitors. Using a clinically isolated ABK-resistant MRSA strain, harboring genes of AAC(6’)-Ie/APH(2”)-Ia, anti-MRSA activities of test samples were measured by the paper disc method, with or without ABK (8 µg/ml – a concentration which has no effect on the growth of MRSA). We screened culture broths of microorganisms to discover those that possessed anti-MRSA activity only in the presence of ABK.
We isolated aranorosin as a circumvention compound of ABK resistance from the culture broth of Gymnascella aurantiaca FKI-6588. Aranorosin (2 µg/ml) enhanced ABK activity against ABK-resistant MRSA 64-fold, decreasing the MIC values of ABK from 16 µg/ml to 0.25 µg/ml. Aranorosin inhibited phosphorylation of recombinant AAC(6’)-Ie/APH(2”)-Ia at 3 µg/ml, but did not inhibit the enzyme acetylation at 100 µg/ml. This result suggests that phosphorylation may be much more critical than acetylation for the inactivation of ABK by the bifunctional modifying enzyme.