Bacterial virulence as a target for antimicrobial chemotherapy

As bacterial resistance to currently used antibiotics increases, so too mus t efforts to identify novel agents and strategies for the prevention and tr eatment of bacterial infection. In the past, antimicrobial drug discovery e fforts have focused on eradicating infection by either cidal or static agen ts, resulting in clearance of the bacterium from the infected host. To this end, drug discovery targets have been those proteins or processes essentia l for bacterial cell viability. However, inhibition of the interaction betw een the bacterium and its host may also be a target. During establishment o f an infection, pathogenic bacteria use carefully regulated pathways of con ditional gene expression to transition from a free-living form to one that must adapt to the host milieu. This transition requires the regulated produ ction of both extracellular and cell-surface molecules, often termed virule nce factors. As the biological imperatives of the invading organism change during the course of an infection, the expression of these factors is alter ed in response to environmental cues. These may be changes in the host envi ronment, for example, pH, metabolites, metal ions, osmolarity, and temperat ure. Alternatively, effector molecules produced by the bacterium to sense c hanging cell density can also lead to changes in virulence gene expression. Although the mechanisms of pathogenesis among different bacteria vary, the principles of virulence are generally conserved. Bacterial virulence may t herefore offer unique opportunities to inhibit the establishment of infecti on or alter its course as a method of antimicrobial chemotherapy.