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Jul 1, 2010 (Vol. 30, No. 13)

Resistant Bugs Necessitate Tougher Tactics

A Handful of Companies Report Progress in Developing Next-Generation Antibacterial Agents

  • Unlocking the Ribosome

    Click Image To Enlarge +
    Rib-X Pharmaceuticals uses structure-based drug design targeted at the ribosome to design novel antibiotics. Linezolid (Zyvox, in purple) and sparsomycin (strong ribosomal binder, in green) are shown in their bound orientations in the ribosome. It was the revelation of the juxtaposition of their binding sites that suggested a validated way to build a next-generation oxazolidinone.

    Rib-X Pharmaceuticals uses structure-based drug design targeted at the ribosome to design novel antibiotics, according to Erin Duffy, Ph.D., vp of structure-based drug design. Because it can delineate how drugs fit into ribosome pockets, 3-D structural modeling facilitates a practical understanding of the binding properties of antibiotics. It also reveals how mutations confer drug resistance. The derived information allows more rational design of novel chemical scaffolds that overcome bacterial resistance.

    Ribosomes translate genetic information into proteins. Soil microorganisms have evolved the ability to produce antibacterial compounds that can block ribosome function. Some of these products have been converted into useful antibiotics that are currently employed commercially. Thus, Mother Nature has validated the ribosome as a suitable target.

    According to Dr. Duffy, structural modeling can provide a clear picture of how each atom of the antibiotic molecule contributes. “In the case of the ribosome, it revealed for the first time how these different antibiotics engage the ribosome. Modeling demonstrated that they do it in adjacent but not overlapping ways. As such, they carve a completely new, validated, and enormous binding site for rational design.

    “Our structural modeling, combined with proprietary computational approaches, allowed us to qualify and quantify high-value interactions these antibiotics make with the ribosome. Selecting any one of these key interaction sites as a starting point, our approach allowed us to build de novo completely new antibiotic scaffolds that take advantage of these interactions. 

    “Listening to the biology, our structure-based design approach can then use the surrounding areas to build-in properties that allow access to bacterial membranes, that afford efficacy in animal models of infection, and that show good safety profiles.”

    Rib-X has three core programs: an empiric first-line treatment, Delafloxacin (a new drug application expected in 2014); Radezolid, a next-generation oxazolidinone (NDA in 2015); and, Rx-04, a broad-spectrum antibiotic that represents a completely new chemical class, active against resistant gram-negative strains (IND 2011).

    “Delafloxacin provides simplified management of complicated infection. Its broad spectrum of coverage and excellent safety profile allows delafloxacin to be utilized as an empiric therapy that does not further compromise ill patients. 

    “Additionally, a second product in Phase II trials, Radezolid provides enhanced coverage, safety, and dosing as compared to linezolid. It concentrates in immune cells and is preferentially delivered to the site of infection. It also shows efficacy at low once-daily doses.”

    The battle of the bug will likely continue for the near future. Trying to outsmart the crafty, adaptive microbes will require more emphasis on drug development such as the creation of novel synthesis strategies, identifying helpful drug synergies, and finding underexploited targets.


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