Impending Doom: Antibiotic Exposure and Bacterial Gene Expression

The discovery of antibiotics ranks as one of the most significant medical achievements of the past century: Antibiotics have greatly attenuated the severity and lethality of bacterial infections. Because antibiotics have been so widely successful, they have been extensively used. This has resulted in strong selective pressure on bacteria that, in turn, has led to the rapid and widespread evolution of antibiotic resistance. Antibiotic resistance now poses a serious threat to the therapy of certain bacterial infections, and new approaches are needed for the development of the next generation of antibiotics. Functional genomics technologies to examine RNA and protein expression levels on a genomewide scale may prove to be important tools for drug discovery research.

In this issue Gmuender et al. (2000) use a functional genomics approach to examine the changes in gene expression that occur in the human respiratory pathogen Haemophilus influenzae upon exposure to the antibiotics ciprofloxacin and novobiocin. Although both of these drugs inhibit bacterial DNA gyrase, they do so by different mechanisms. Novobiocin is a coumarin antibiotic that binds to the ATP binding site of the B subunit of gyrase and inhibits the supercoiling activity of the enzyme. Because transcription is known to be sensitive to the state of supercoiling, novobiocin may affect the transcription of many genes. In contrast, ciprofloxacin is a quinolone that binds to the A subunit of gyrase and interrupts the DNA cleavage and resealing activity of the enzyme. The failure to seal doublestrand breaks results in DNA damage and quinolones are known to induce DNA repair systems (Piddock et al. 1990). Thus, the two drugs may elicit different physiological responses despite binding to the same target.

A distinguishing feature of this work is that Gmuender et al. (2000)examine gene expression at the level of transcription with microarrays and translation using …