Frequent use of aminoglycoside antibiotics in the treatment of serious Gram-negative infections

Frequent use of aminoglycoside antibiotics in the treatment of serious Gram-negative infections has been accompanied by the emergence of multiple drug-resistant strains of bacteria carrying R-factors. This has stimulated the study of resistance mechanisms and mechanisms for circumventing the drug inactivation caused by resistant bacteria. Thus, aminoglycoside antibiotics have been chemically modified in various ways to make them resistant to enzymatic inactivation. One approach is the elimination of the hydroxy groups which are targets for enzymatic attacks, yielding, for example, 3',4'dideoxykanamycin B2'. Acylation of the 1-amino group with L-4-amino-2-hydroxybutyric acid (LAHBA) or its congeners, as exemplified by amikacin2", produces a pronounced effect against inactivation by many aminoglycoside-modifying enzymes. It has been reported recently that 1-N-ethylation of sisomicin was effective in making the antibiotic active against sisomicin-resistant organisms. This semisynthetic sisomicin derivative is called netilmicin4'. We have studied the N-alkylation of kanamycins A and B to explore the effect on enzymatic inactivation. This paper describes the preparation and activity of N-ethyl derivatives of kanamycin and discusses structure-activity relationships for both sensitive and resistant organisms.