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Reducing the Binding Affinity

Another approach involves modifying the antibiotic in such a way that it can no longer bind to the aminoglycoside-modifying enzymes. This strategy is based on the observation that the naturally occurring butirosins, which possess a 4-amino-2-hydroxybutyryl (AHB) group on the amine at the 1-po-sition of the 2-deoxystreptamine ring, are resistant to many inactivating enzymes, yet retain their bactericidal properties (Tsukiura et al. 1973) (Fig. 6a). It is thought that the AHB and other side chains at the 1-amino position hinder binding to the aminoglycoside-modifying enzyme (Kondo and Hotta 1999). This observation led to the development of second generation semisynthetic aminoglycoside antibiotics such as amikacin (Fig. 6b) and arbekacin (kanamycin A and dibekacin derivated at the N1 by an AHB group, respectively) (Kawaguchi et al. 1972; Kondo et al. 1973a,b; Holm et al. 1983), isepamicin (Fig. 6c) (gentamicin B substituted with a 4-amino-2-hy-droxypropionyl at N1) (Nagabhushan et al. 1978), as well as netilmicin (siso-micin with ethyl group introduced at N1) (Wright 1976). They have been shown to be clinically useful, especially arbekacin, which is effective against MRSA infections (Kondo and Hotta 1999) and whose antibiotic activity is unaffected by 2'- and 3''-acetylation (Hotta et al. 1996, 1998). Unfortunately, some level of resistance has been noted, chiefly as a consequence of inactiva-tion by the bifunctional enzyme AAC(6')-Ie-APH(2'')-Ia (Kondo et al. 1993b; Fujimura et al. 1998; Fujimura et al. 2000). Subsequently, two derivatives of arbekacin, 200-amino-200-deoxyarbekacin and 200-amino-5,200-dideoxy-5-epi-aminoarbekacin (Kondo et al. 1993a, 1994), have been developed and shown to be active in vivo, yet less toxic to mammals than their parent compound (Inouye et al. 1996).

Another scheme for diminishing the binding affinity of aminoglycosides for APHs is by minimizing the electrostatic interactions between the amino-glycoside and the resistance enzyme. This is achieved through the deletion of amino or hydroxyl groups at important positions on neamine and kana-mycin B (Roestamadji et al. 1995a; McKay et al. 1996). These modified drugs retain their antibacterial activity but have a significantly reduced rate of phosphorylation and affinity for APH(30)-Ia and APH(30)-IIa, probably due to the removal of specific ionic and hydrogen bond interactions between the

Fig. 6 Three aminoglycosides with substitutions at the 1-amino group of the central 2-de-oxystreptamine ring. Butirosin is naturally occurring, while amikacin and isepamicin are semisynthetic aminoglycosides. The 1-amino substitutions are believed to hinder binding to aminoglycoside-modifying enzymes, making these compounds resistant to inactiva-tion

Fig. 6 Three aminoglycosides with substitutions at the 1-amino group of the central 2-de-oxystreptamine ring. Butirosin is naturally occurring, while amikacin and isepamicin are semisynthetic aminoglycosides. The 1-amino substitutions are believed to hinder binding to aminoglycoside-modifying enzymes, making these compounds resistant to inactiva-tion substrate and the enzyme. However, the affinity of these analogues for APH(3')-IIIa is only moderately affected.

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