By changing the location of a single bump on this antibiotic, researchers were able to block bacteria’s resistance to it.Li et al. / Nature
Multi-pronged attack — The team focused in on a member of the streptogramin antibiotic family, Virginiamycin M2 (VM2), which uses a two-pronged attack to adhere to and inhibit the growth of bacteria.
Bacteria that have developed resistance to this antibiotic do so by binding to it and forcing it to grow a small little bump that prevents it from easily sliding into place in the bacteria’s ribosomes. Without this first prong successfully landing, the second one becomes ineffective as well, and so the bacteria proliferate.
To overcome this problem, the researchers decided to reverse-engineer the antibiotic molecule to essentially use the same tactic against the bacteria.
When done by the bacteria, enzymes deactivate and reshuffle different parts of the molecules’ chemical make-up to cause its bump. In their study, the researchers found a molecule that mirrors this same bump mechanism and used it to place the bump at the other end of the antibiotic. The switch means the bacteria can’t bind with the antibiotic, thus stopping them from switching the molecules’ chemical make-up. As a result, the antibiotic was able to carry-out its two-pronged attack on the bacteria’s ribosome without a problem.
To test how effective this strategy was in a real, living organism, the researchers looked at how their solution would fair against streptogramin-resistant strains of Staphylococcus aureus in mice. They found the re-imagined antibiotics were effective at lowering the overall bacterial load in these mice.
What’s next — The study is in mice and the findings can’t be translated to humans. The results are promising, but the researchers caution their strategy isn’t necessarily a permanent solution to antibiotic resistance. Rather, it could help extend the usefulness of certain antibiotics while researchers continue to design new ones.
“Although the emergence of other resistance mechanisms is inevitable, this approach may permit chemical adaptations to extend the clinical longevity of the streptogramin class,” write the authors.
The next step will be to conduct more animal and, eventually, human trials to determine the clinical potential of such an approach. But the companion report authors suggest the innovative use of chemistry in this study will move the needle forward for the field nonetheless.
“More broadly, this story will embolden the pursuit of modular, complex small molecules as engines for pushing the frontiers of chemical biology and drug discovery,” they write.
Abstract: Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.