Protein kinase inhibitors and antibiotic resistance

Abstract

While antibiotics revolutionized the treatment of infectious disease in the 20th century, bacterial resistance now threatens to render many of them ineffective. Aminoglycosides are a class of clinically important antibiotics used in the treatment of infections caused by Gram-positive and -negative organisms. They are bactericidal, targeting the bacterial ribosome, where they bind to the A-site and disrupt protein synthesis. Clinical resistance to these drugs occurs mainly via enzymatic inactivation by aminoglycoside-modifying enzymes that phosphorylate, adenylate, or acetylate the aminoglycoside. Those that phosphorylate (i.e., aminoglycoside kinases) have been shown to be structurally related to eukaryotic protein kinases. This was surprising, given the low degree of sequence similarity between the groups of enzymes. The nucleotide-binding site, specifically, is very similar in structure, suggesting that the two classes of enzymes share a common mechanism of phosphoryl transfer. Three strategies can be envisaged for combating aminoglycoside kinase-mediated bacterial resistance. The first involves compounds that target the antibiotic binding region. Secondly, protein kinase inhibitors have been identified that disable aminoglycoside-modifying enzymes by targeting the ATP-binding site. Lastly, compounds are being developed that exploit the bridged nature of the active site, incorporating nucleotide and substrate motifs. A strategy using bifunctional aminoglycoside dimers has also been pursued, yielding molecules that bind to the target site on the bacterial ribosome, while serving as poor substrates for modifying enzymes. This work holds out the promise that effective inhibitors of aminoglycoside-modifying enzymes may eventually restore the usefulness of aminoglycoside antibiotics.