Inhibition of Virulence Factors in Bacteria

Abstract: The ongoing spread of antibiotic resistance is seriously undermining the present alternatives for therapeutic intervention against human infectious disease. The incidence of antimicrobial resistance among pathogenic bacteria causing the most prevalent nosocomial and community acquired infections is extending to often affect the drugs of choice for their treatment. Since most of the newly introduced drugs are modifications of antimicrobials in use, their usefulness is sometimes limited by the emergence of resistance. Therefore, it becomes important to search and develop new targets for antimicrobial therapy. Bacterial virulence factors offer an attractive opportu­ nity for therapeutic intervention against infectious diseases. The success of modern vac­ cines against serious bacterial diseases demonstrates that neutralization of virulence factors is successful in controlling and terminating infections. Furthermore, an increasing number of genetic studies with a variety of pathogenic bacteria in animal models of infection show that alterations that result in failure to express virulence factors prevent bacteria to survive within the host. Thus, the outlook for the effectiveness of therapeutic approaches that may target expression of virulence factors in bacteria appears quite favorable. Many antimicrobials as well as other drugs show diverse inhibitory effects on the expression of virulence factors in vitro, and sometimes even in vivo. Although these studies fail to characterize in any detailed manner the nature of the effects, they indicate that small molecules may be used to inhibit virulence factors. The recent discovery of inhibitors of global regulatory systems whose components' structure are highly conserved among bacteria of different species and which control the expression of virulence factors, has kindled interest in these mechanisms as potential pharmaceutical targets. Furthermore, the existence of common structural motifs among components of bacterial protein export and secretion systems used for virulence factors should also make these systems attractive targets for therapeutic intervention.