Aminoglycosides strategies

The different 3D-shapes adopted by aminoglycosides in the RNA- and enzyme-bound states suggest a possible structure-based chemical strategy to obtain antibiotics with better activity against resistant bacteria. Assiun-ing that, in these cases, some degree of conformational distortion of the substrates is required for enzymatic activity, it should be possible to design a conformationally locked oHgosaccharide that still retains antibiotic activity, but that is not susceptible to enzymatic inactivation (Fig. 8) [41]. 

Aminoglycoside resistance has been a powerful impediment to the continued use of these potent antibacterial agents. The myriad of strategies that confer resistance... 

Figure 4.2. General strategies for the synthesis of neomycin and kanamycin classes of aminoglycosides.

Attaching fnnctionalities at the N-1 position of the 2-deoxystreptamine among kanamycin or neomycin class antibiotics, is one of the other most effective methods of reviving the activity against aminoglycoside resistant bacteria. This strategy has led to the development of semisynthetic amikacin that has an (5 )-4-amino-2-hydroxybutyryl (AHB) group at N-1 position. 

New concepts in the strategy of the synthesis of drugs rarely appear, such as from the observation that microorganisms often get resistance from enqrmes that inactivate the drug through phosphorylation. To avoid the problem, the aminoglycoside antibiotic kanamycin A was modified in a way that it was re-obtained whenever it was modified by the microorganism resistance enzymes (Haddad 1999). 

The facile formation of the iodo compound, and the subsequent reduction with tributyltin hydride opens a new access to 2-amino-2,3-dideoxy-D-glucose (D-lividosamine) present in various aminoglycoside antibiotics [92], The same strategy been used in the synthesis of C-lO -C-l fragment of boromycin [93]. Displacement of the C-3 imidazylate ester of a 2-azido-2-deoxy-a-D-altropyranose derivative with benzoate occurred readily [94], compared with the corresponding tosylate [95],... 

Nagai J, Takano M. Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet. 2004 19 159-170. 

Park WKC, Auer M, Jaksche H, Wong CH, Rapid combinatorial synthesis of aminoglycoside antibiotic mimetics use of a polyethylene glycol-linked amine and a neamine-derived aldehyde in multiple component condensation as a strategy for the discovery of new inhibitors of the HIV RNA Rev responsive elements, J. Am. Chem. Soc., 118 10150-10155, 1996. 

Food safety concerns were also addressed via IPC. Many veterinary drugs were controlled in a broad range of food matrices. For example, a specific IPC strategy was developed for routine determination of the marker residues of oxytetracycline in edible animal tissues [36]. Dihydrostreptomycin is an aminoglycoside antibiotic used in veterinary medicine in combination with benzylpenicillin to treat bacterial infections in cattle, pigs and sheep its IPC quantitative determination in bovine tissues and milk was developed and optimized [37,38]. 

From these examples it is clear that nature also provides convergent alternatives to the linear assembly of deoxysaccharides, as was, for example, observed in tylosin [90] or streptomycin (24) biosynthesis [72], A linear strategy is certainly also true for other aminoglycosides, although in the case of neomycin biosynthesis, an alternative disaccharyl transfer has been discussed [70],... 

Phosphorylation is a common mechanism resulting in resistance to the aminoglycoside antibiotics. This chemical strategy also has been associated with resistance to the macrolides such as erythromycin, the tuberactinomycins such as viomycin, and chloramphenicol. The aminoglycoside kinases share 3D structural similarity with the Ser/Thr/Tyr protein kinase family (36), and the conservation of kinase signature sequences in macrolide... 

Strategies for minimizing aminoglycoside toxicity include early bedside detection of cochlear and vestibular dysfunction, which should lead to prompt withdrawal, use of short periods of treatment, dosing intervals of at least 12 hours, monitoring of serum concentrations, and awareness of relative contraindications, such as renal or hepatic dysfunction, old age, hearing impairment, and previous recent aminoglycoside exposure (3). 

Table 1. Strategies to prevent aminoglycoside-induced nephrotoxicity.

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