Aminoglycosides are one of the largest and most common classes of antibiotics we use on a daily basis. The founding member of this group, Streptomycin, was discovered early in the golden age of antibiotics and was the first antibiotic found to be efficacious in treating tuberculosis. In the decades that followed, many new aminoglycosides were discovered or synthetically developed, including: kanamycin, spectinomycin, amikacin, apramycin and hygromycin. These drugs have been a bulwark of our antibiotic armament over the years due to their effectiveness against both gram positive and gram negative bacteria, their synergism with other antibiotic classes and their generally low cost. But as with all antibiotics, organisms have been developing resistance to them as fast as we have been able to develop new variants.
There are three main methods by which organisms have gained resistance to aminoglycosides: decreased intracellular concentration due to active efflux of the antibiotic (as with lung isolates of P. aeruginosa), targeted modifications of genes like rpsL or rrs which change their protein structure slightly, but significantly, and most commonly by enzymatic modification by aminoglycoside-modifying enzymes (AMEs). AMEs change the structure of the aminoglycoside which then prevents their binding to the ribosome. One of the ways AMEs does this is through APHs (nucleoside triphosphate-dependent phosphotransferases). There are over 100 different AMEs described in literature, and 40 crystal structures of 8 different APH enzymes have been analyzed, demonstrating the diversity and variability of this class of enzymes.
The primary, historical method of circumventing AME-mediated resistance has been in the creation of steric hindrance. In this process, the inclusion of precisely placed side chains such as AHB ((S)-4-amino-2-hydroxybutyrate) offer resistance to the actions of many AMEs, a process that has worked effectively in creating new antibiotics like amikacin from kanamycin. Even more recently, Plazomicin has been synthesized by the addition of an AHB group (to position 1 of the 2-deoxystreptamine) and a hydroxyethyl group (to position 6’) to the sisomicin molecule. The effect is an aminoglycoside which appears to be resistant to all but one aminoglycoside resistance enzymes (the exception was AAC(2’)) (Armstrong and Miller, 2010)! There have also been a few others which have shown some efficacy against resistant strains, but in the greater war, that’s not a lot of reserve options. And AMEs are certain to coevolve equally fast with these new antibiotics.
An ideal APH would provide resistance against all members of the AME family. However, that might not be feasible as we learn more about the structures of the different subfamilies of APH enzymes. Researching more specific APH inhibitors might be more useful, but would likely prove less profitable. Considering our inability to produce a lot of next-generation aminoglycosides, however, perhaps specific APH inhibitors are a better choice after all if we want to slow down the impending ARA (Antibiotic Resistance Apocalypse). You can find a more complete review of this subject online from Kun Shi and associates from McGill University.
Shi, K., Caldwell, S. J., Fong, D. H., & Berghuis, A. M. Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance. Frontiers in Cellular and Infection Microbiology, 3, 22.
Armstrong, E. S., and Miller, G.H. (2010). Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr.
Opin. Microbiol. 13, 565–573.
Category Code: 79101