Double Stage Activity in Aminoglycoside Antibiotics.

Abstract

Fourteen different aminoglycoside antibiotics (AGs) were challenged with aminoglycoside acetyltransferases (AACs) of actinomycete origin in order to examine their 'double stage activity' that is arbitrarily defined as antibiotic activity retainable after enzymatic modification. In kanamycin (KM)-group AGs tested [KM, dibekacin (DKB), amikacin and arbekacin (ABK)], ABKretained activity after acetylations by AAC(3), AAC(2') and AAC(6'). DKBalso retained a weak activity after acetylation by AAC(2'). In gentamicin (GM)-group AGs tested [GM, micronomicin, sisomicin (SISO), netilmicin (NTL) and isepamicin], GM, SISO and NTL retained activites after acetylation by AAC(2'). In neomycin (NM)-group AGs tested

Revisiting the Nucleotide and Aminoglycoside Substrate Specificity of the Bifunctional Aminoglycoside Acetyltransferase(6′)-Ie/Aminoglycoside Phosphotransferase(2″)-Ia Enzyme

“…As anticipated, the high catalytic efficiency of the enzyme against most 4,6-disubstituted aminoglycosides translates into a 64 -128-fold increase in the MICs of these antibiotics over background levels (Table 1) Ϫ1 s Ϫ1 , respectively, the enzyme does not confer resistance to these antibiotics. Previous studies have demonstrated that arbekacin acetylated at the 3-, 2Ј-, or 6Ј-positions retains antibiotic activity against Gram-positive and Gram-negative bacteria, despite modification (27,28). Our data suggest that the product of arbekacin phosphorylation may also retain antibacterial activity.…”

Trends of Arbekacin-resistant MRSA Strains in Japanese Hospitals (1979 to 2000)

“…Resistance levels were determined by the agar dilution method using Mueller Hinton II medium (Becton Dickinson, Franklin Lakes, NJ) containing AG at concentrations of 0 to 100 m g/ml as described previously [6].…”

“…The enzymes differ in their substrate specificity and are named according to the site that they modify on the antibiotic molecule. In MRSA, five AME-encoding genes, aph(3Ј), aad(4Ј,4Љ), aad (6), aph (9), and aac(6Ј)/aph(2Љ), have been reported [3]. In particular, the bifunctional enzyme, AAC(6Ј)/APH(2Љ), is of therapeutic importance because it is able to modify arbekacin (ABK), which is an anti-MRSA drug used in Japan [4,5].…”

“…Recently, we reported the distinctive features of ABK against modification by AMEs [6]. Although ABK can be acetylated by AG acetyltransferases (AACs), acetylated products retain substantial antibiotic activity to inhibit bacterial growth.…”

Aranorosin circumvents arbekacin-resistance in MRSA by inhibiting the bifunctional enzyme AAC(6′)/APH(2″)

“…It was reported that ABK retained antimicrobial activity after enzymatic acetylation by AAC(3), AAC(2 0 ) and AAC(6 0 ). 15 Kondo et al 6 reported that when ABK was inactivated by crude enzyme prepared from an ABK-resistant MRSA having AAC(6 0 )/APH(2 00 ), phosphorylated ABK was obtained as a major inactivated product. Therefore, phosphorylation may be much critical than acetylation for the inactivatiton of ABK.…”