New antibiotic nearly eliminates the chance of superbugs evolving
Researchers have combined the bacteria-killing actions of two classes of antibiotics into one, demonstrating that their new dual-action antibiotic could make bacterial resistance (almost) an impossibility.
newatlas.com
Researchers have combined the bacteria-killing actions of two classes of antibiotics into one, demonstrating that their new dual-action antibiotic could make bacterial resistance (almost) an impossibility.
Pathogens such as bacteria threaten human health, so we dole out antibiotics. The bacteria then develop resistance to the antibiotics. While bacterial threat remains the same, our treatment arsenal is less effective, if it's effective at all. In essence, that's the problem caused by antibiotic resistance.
But now, researchers from the University of Illinois Chicago (UIC) may have replenished the arsenal with a new antibiotic, one that could make it nearly impossible for bacteria to develop resistance to.
"The beauty of this antibiotic is that it kills through two different targets in bacteria," said Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC and the study's co-corresponding author. "If the antibiotic hits both targets at the same concentration, then the bacteria lose their ability to become resistant via [the] acquisition of random mutations in any of the two targets."
The class of antibiotics called macrolides have been used for decades to treat various bacterial infections. You can tell a macrolide antibiotic because they end in '–mycin'. Erythromycin, for example. Chemically, macrolides are composed of a macrolactone ring decorated with side chains. They stop bacterial growth by binding to the bacteria's ribosome, its protein-producing machinery, inhibiting protein synthesis.
Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms - Nature Chemical Biology
Hybrids of macrolides and quinolones, called macrolones, can overcome macrolide-induced resistance through new interactions between the quinolone moiety and the ribosome and can concurrently inhibit both ribosome and DNA gyrase targets.
www.nature.com
Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.
