Targeting virulence not viability in the search for future antibacterials

Abstract

New antibacterials need new approaches to overcome the problem of rapid antibiotic resistance. Here we review the development of potential new antibacterial drugs that do not kill bacteria or inhibit their growth, but combat disease instead by targeting bacterial virulence.

Keywords: antibacterial; antivirulence; bacterial infection; pilicide; quorum sensing.

Figure 1

Antibiotics and antivirulence agents. Antibiotics (left) kill bacteria or prevent their growth. Antivirulence agents (right) render bacteria harmless by blocking the activity of virulence factors. Virulence factors can include toxins (denoted by poison sign), secretion systems (syringe), adhesion factors (grappling hook) or quorum sensing (walkie-talkie), amongst others

Figure 2

Examples of bacterial virulence pathways that have been targeted for antimicrobial development. Bacterial adhesion to the host cell; 1. Inhibitors of pili biosynthetic machineries (e.g. chaperone/usher pathway); 2. Inhibitors of the carbohydrate-binding sites in the adhesin molecules. Bacterial secretion systems; 3. Inhibitors of the type three secretion system (TTSS) to block injection of effector proteins to the host cell. Toxin production; 4. Toxin neutralization to inhibit damage to the host. Acyl-homoserine lactone (AHL) mediated quorum sensing (QS): 5. Inhibitors of AHL synthase LuxI. 6. AHL degrading enzymes (e.g. lactonase and acylase). 7. Inhibitors of AHL binding to transcriptional regulator LuxR

Figure 3

Schematic representation of the DSB catalytic cycle. Quinones (labelled Q) generate disulfides in DsbB (orange), which are transferred to DsbA (green), which catalyzes oxidative protein folding in substrate virulence factors (blue; and indicated above). In concert, the disulfide in DsbA (labelled S-S) is reduced to two thiols (labelled SH) to complete the catalytic cycle