Experimental Determination of the pK_a Values of Clinically Relevant Aminoglycoside Antibiotics: Toward Establishing pK_a─Activity Relationships

Abstract

Investigating the relationship between individual pK a values and the efficacy of aminoglycosides is essential for the development of more effective and targeted therapies. In this work, we measured the pK a values for individual amino groups of the six clinically relevant aminoglycoside antibiotics gentamicin, tobramycin, amikacin, arbekacin, plazomicin, and apramycin using 15 N− 1 H heteronuclear multiple-bond correlation and 1 H NMR experiments. For arbekacin and plazomicin, the pK a values are reported for the first time. These pK a values were used to calculate the net charges of the aminoglycosides and the protonation levels of amino groups under various pH conditions. The results were analyzed in relation to the mode of interaction and inhibition to establish pK a relationships for rRNA binding, inhibitory activity, and the pH dependence of the uptake into bacterial cells.