Aminoglycosides enzymatic inactivation

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]. 

In order to analyze the effect that conformational restriction has on the antibiotic enzymatic inactivation, three different enzymes were chosen as model systems Staphylococcus aureus ANT(4 ), Mycobacterium tuberculosis AAC(2 ) and Enterococcus faecalis APH(3 ). These proteins are representative of the three main families of enzymes that modify aminoglycosides adenyltrans-ferases, acyltransferases and phosphotransferases. In addition, there is high resolution X-ray structural information available for the three enzymes in complex with several antibiotics. 

Enzymatic Inactivation (e.g.. Hydrolysis) Covalent Modification Oxidation/Reduction P-Lactams, Fosfomycin Aminoglycosides, Chloramphenicol Tetracycline... 

Figure 18 Enzymatic inactivation of ciprofloxacin by N-acetylation catalyzed by the aminoglycoside acetyltransferase AAC(6 )-lb enzyme.

Neomycins, Paromomycins, Lividomycins. Although the tetra- and pen-tacyclic aminoglycosides have been known for some time (neomycin 1949, paromomycin 1959, lividomycin 1967), only a few chemical modifications have been carried out. Not until after the discovery of the enzymatic inactivation mechanisms were several deoxy compounds and acylated derivatives (HABA, etc.) prepared. 

Substantial progress towards the improvement of the activity of the aminoglycosides was made by the clarification of the enzymatic inactivation mechanisms of aminoglycoside by resistant organisms. The formation of those enzymes which inactivate aminoglycosides is determined by episomal genes. This type of resistance is therefore called episomal resistance or R-factor mediated resistance, which can be transferred between bacteria cells, but not by spontaneous mutation. 

E. Aminoglycoside antibiotics have several well-characterized modes of enzymatic inactivation and all clinical isolates of bacteria resistant to these antibiotics have been shown to possess these inactivation mecha-... 

At the present time, three different mechanisms are known by which aminoglycoside antibiotics can be enzymatically modified and inactivated ... 

---