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Novel Approaches to Combating Bacteria

The worldwide emergence of bacteria that are resistant to available antibiotics threatens to undo the dramatic advances in human health witnessed in the second half of the last century. This development is especially troubling considering that no new class of antibiotic has been introduced in over two decades. As a result, it is critical to understand the molecular origins of resistance. For antibiotics derived from natural products (i.e. vancomycin), resistance is most often due to the acquisition of genes from other bacteria that encode enzymes capable of inactivating the antibiotic, modifying its target, or increasing its export out of the cell. However, enzymes that modify synthetic antibiotics such as quinolones, sulfonamides, and trimethoprim do not exist in nature, and resistance to these antibiotics requires mutation of genes already present in the bacterial genome.

 
Under the stress of being exposed to a given antibiotic, upregulation of genes, such as those encoding error prone polymerases, leads to the introduction of mutations that may confer antibiotic resistance. We have studied this process using Escherchia coli and the antibiotics ciprofloxacin and rifampicin, and we have identified several interesting targets whose inhibition might prevent the induced mutation process. E. coli treated with ciprofloxacin are very elongated (left). Shown below is the model we propose for how E. coli responds to ciprofloxacin. Click here to read more.
We have also established high throughput screening methodologies to identify inhibitors of the these target proteins. Such compounds might eventually be developed into drugs that when administered in conjunction with an antibiotic, prevents the development of resistance by inhibiting the mutation process. This work is done in collaboration with Achaogen, Inc .

In addition to E. coli, we are working with Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus. We have constructed a number of mutants of these pathogenic organisms. At right is an image of a S. aureus rexAB mutant, visualized with DAPI (which binds to DNA). Loss of the exonuclease/helicase, RexAB (the functional homologue of E. coli RecBCD) results in large aggregates of cells.

In collaboration with TIGR's Pathogen Functional Genomics Resource Center, we are investigating the response of these pathogens to antibiotics and learning how different genes contribute to the response.