Resistance and tolerance to aminoglycosides

Aminoglycosides (AGs) are a class of broad-spectrum, ribosome-targeting antibiotics that have been the mainstay of modern medicine for over 70 years. As the clinical and agricultural uses of AGs has increased, so has the capacity of bacteria to evade their activity. Bacteria can deploy a variety of resistance mechanisms to alter their ribosomal RNA or directly modify AGs to prevent corruption of ribosomal activity. Further, bacteria can acquire genetic mutations or enter into non-heritable phenotypic states that limit intracellular AG accumulation through enhanced efflux or reduced uptake. Until recently, resistance combined with adverse side effects have reduced incentives to develop new AG derivatives; however, the increasing incidence of multidrug-resistant microorganisms has generated renewed interest in AGs. Recent discoveries that AGs can be used to eradicate bacterial persisters further exemplify the utility of this class of drugs in combatting chronic infections. In this chapter, we focus on bacterial resistance and tolerance toward AGs and on-going research on methods to overcome these bacterial defensive mechanisms. Increased efforts in developing novel AG structural analogues, adjuvants, and alternative delivery methods are expected to enhance the clinical efficacy and safety of this important class of drugs.