Chapter 11:Amphiphilic Aminoglycoside Antimicrobials in Antibacterial Discovery

Amphiphilic aminoglycoside antimicrobials (AAAs) are an emerging class of polycationic antibacterial agents with broad-spectrum antibacterial activity. In contrast to aminoglycosides, which interfere with protein synthesis by interacting with the 30S ribosomal subunit, AAAs appear to target the bacterial cell wall by interactions with extracellular lipids or proteins or by enhancing the permeability of the bacterial cell wall. The physicochemical similarities between amphiphilic aminoglycosides and antimicrobial peptides, another class of polycationic amphiphiles with broad-spectrum antibacterial activity, suggest similar mode(s) of action. However, in contrast to antimicrobial peptides, AAAs are not composed of peptide bonds and as such promise to display superior metabolic stability. As a result, AAAs may be considered to be a novel class of antimicrobial peptidomimetics. Many AAAs possess impressive potent antibacterial activity against Gram-positive and Gram-negative bacteria, especially against bacterial strains that are resistant to clinically used antibiotics. In summary, AAAs promise to provide a new and rich source of antibacterial lead structures to combat antibiotic-resistant and multidrug-resistant pathogens.