FIG. 5.

Potential strategies to overcome or avoid inactivation of aminoglycosides by APH(3′) enzymes (see Fig. 3 for the site of action these enzymes). 5A, reduction of the electrostatic binding of the drug to the enzymes by deamination of the 6′ position and/or the 1 and 3" positions; 5B, design of a suicide substrate (2′-nitro derivative allowing for the formation of a 2′-nitro, 3′-phospho derivative which then gives rise to a highly reactive 2′-nitroalkene capable of inactivating the enzyme by chemical binding to amino acids close to the active site); 5C, design of analogues of the pentacoordinate transition state compound involved in the enzymatic phosphorylation of the drug; 5D, use of inhibitors of protein kinases based on the similarities between these enzymes and APH(3′)-IIIa.