Novel antimicrobial class.

Bacterial adaptation makes antibacterial drug resistance inevitable. As old medicines lose their effectiveness, scientists must find new drugs that can safely treat a broad spectrum of bacterial infections. For more than 30 years, the problem has been addressed by improving old classes of drugs. However, with this approach, we stay just ahead of the evolving bacteria; and the strategy becomes more difficult with each iteration. No truly new classes of orally active, broad-spectrum antimicrobial agents have been discovered since quinolones. A class of broad-spectrum novel ribosome inhibitors (NRI) has been found that shut down bacterial protein synthesis. Although many existing antimicrobial agents act against the ribosome, the NRIs exploit a new mechanism of action. Because bacterial populations are not familiar with NRIs, no preexisting resistance mechanisms exist in bacteria, and NRIs have consistent antimicrobial activity even against multiple drug-resistant strains.

The team conducted a comprehensive series of biologic and biochemical experiments to discover and characterize the new class, as recently reported in the journal Antimicrobial Agents and Chemotherapy. NRIs inhibit ribosomes of both gram-positive and -negative pathogenic bacteria but will not disturb eukaryotic protein synthesis. Furthermore, the new compounds inhibit bacterial growth without toxicity to human cells, consistent with developing a new drug that kills bacteria without disturbing the human host. As further evidence of the ribosomal mechanism, the group showed that bacteria treated with NRI compounds respond by trying to overproduce ribosomal proteins. As with other ribosome inhibitors, the bacteria seem to realize that their ribosomes are failing, and they desperately try to make more to survive. In the laboratory, bacteria could be made less susceptible to NRIs by certain mutations in their ribosomes. Although, fortunately, these mutations would be difficult to generate outside the laboratory, they were useful in supporting the novel mechanism of action, since these genetic alterations did not affect the action of other ribosomal drugs. The recent data hold hope for new antimicrobial agents that can combat the rising tide of microbial resistance.

Dandliker PJ, Pratt SD, Nilius AM, Black-Schaefer C, Ruan X, Towne DL, et al. Novel antibacterial class. Antimicrob Agents Chemother. 2003;47:3831-9.

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