The biology and future prospects of antivirulence therapies

Abstract

The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.

Figure 1. Multi-step pathogenic cascade of uropathogenic Escherichia coli (UPEC)

UPEC coordinate highly organized temporal and spatial events to colonize the urinary tract. UPEC bind to and invade the superficial facet cells that line the bladder lumen, where they rapidly replicate to form a biofilm-like intracellular bacterial community (IBC). In the IBC, bacteria find safe haven, are resistant to antibiotics and subvert clearance by host innate immune responses. UPEC can persist for months in a quiescent bladder reservoir following acute infection and challenge current antimicrobial therapies. Quiescent bacteria can re-emerge from their protected intracellular niche and be a source of recurrent urinary-tract infections. Insight into the processes that accompany IBC formation and biofilm dispersal, as well as the factors that drive bacteria into the reservoir, may aid the design of preventive or therapeutic strategies for recurrent infections.

Figure 2. Targeting microbial adhesion

a | Pathogenic Escherichia coli use type 1 pili to bind to hexameric uroplakin protein arrays on the surface of superficial facet cells that line the bladder lumen. Type 1 pili mediate the binding to, and subsequent invasion of, these cells. b | Pyridone-based pilicides inhibit pilus biogenesis by disrupting chaperone–usher protein interactions and dramatically reduce piliation levels. Image on the left in panel a reproduced, with permission, from REF. © (1995) National Academy of Sciences. Image on the right in panel a reproduced, with permission, from REF. © (1998) American Association for the Advancement of Science. Images in panel b reproduced, with permission, from REF. © (2006) National Academy of Sciences.

Figure 3. Targeting toxin-powered pathogens

a | The inhibition of toxin transcription, as described for Vibrio cholerae, is one way to inhibit the consequences of toxin-mediated virulence. b | Neutralizing toxins, or preventing their trafficking and/or enzymatic activity, at cellular targets is an alternative strategy to inhibit toxin damage to the host.

Figure 4. Pairing quorum sensing and two-component signaling in the staphylococcal agr system

Staphylococcus aureus uses a two-component response system (TCRS) to mediate quorum sensing (QS). The regulation of QS involves the production of an autoinducer and an increase in its concentration, expression of RNAIII and the subsequent regulation of QS genes. S. aureus produces an autoinducing peptide (AIP) that accumulates extracellularly and activates the TCRS. The TCRS involves signal recognition by a histidine kinase (AgrC) (1), followed by histidine phosphorylation (2) and phosphotransfer to a response regulator (AgrA) (3), which then binds to the RNAIII transcript that encodes a small RNA that functions to modulate gene expression of S. aureus genes (4).