An Alternative Strategy as Quorum-Sensing Inhibitor: Pheromone-Guided Antimicrobial Peptides

Abstract

Mankind fights microbial infections worldwide by using large quantities of antimicrobials (Geddes 2000). The success of these therapies in infectious diseases is largely based on the availability of antimicrobials that aim to kill target pathogens (Kohansk et al. 2010). Indeed, many bacterial infections can be treated effectively with antibiotics since Alexander Fleming discovered the first antibiotic penicillin in 1928 (Andersson and Hughes 2010). In the battles of fighting against microbial infections today, however, we have found ourselves facing a severe threat: many antibiotics have lost their effectiveness in treating infectious diseases due to the growing crisis of development of antibiotic-resistant microorganisms (Hogan and Kolter 2002; Hughes and Anderson 2012). Meanwhile, many conventionally available antimicrobials exhibit broad-spectral killing with regard to bacterial genera and species (Eckert et al. 2006). Such indiscriminate killing of microbes can disrupt the ecological balance of the indigenous microflora in a natural ecosystem, resulting in various negative clinical consequences (Eckert 2011). The problems resulting from broad-spectrum antimicrobials combined with the emergency of antibiotic resistance highlight the urgent need for new antimicrobials that selectively target specific pathogens but less likely promote antibiotic resistance. Currently, there are at least two major research areas where researchers aim to discover such new antimicrobials as alternatives. In one field, antimicrobial peptides (AMPs) have been rigorously investigated as alternatives to small-molecule antibiotics, mainly because of their ability to kill antibiotic-resistant pathogens (Jenssen et al. 2006; Brogden and Brogden 2011). In another field that is extensively studied in recent years, scientists actively search for natural and synthetic compounds that act as quorum-sensing inhibitors (QSI) targeting bacterial cell-cell signaling and its controlled pathogenic activities (LaSarre and Federie 2013). These compounds that quench quorum-sensing mechanisms are considered as promising alternatives to antibiotic-resistant microbes (Kalia and Purohit 2011). It is believed that QSIs target bacterial cell-cell signaling and coordinated activities required for infections, thereby, essentially disarming the bacteria and tipping the balance in favor of the host and allowing the immune system to clear the infectious pathogen (Li and Tian 2012). QSI therapies that specifically block bacterial quorum sensing can make the pathogens become “deaf,” “mute,” or “blind” rather than directly kill them. Therefore, QSI therapy may achieve the treatment but cause much less selective pressure to create resistant microbes (LaSarre and Federie 2013; Kalia 2013). More recently, a new class of antimicrobials, called pheromone-guided antimicrobial peptides (PG-AMP), has been developed as potential alternatives (Eckert et al. 2006a, b; Mai et al. 2011; Qiu et al. 2003, 2005). PG-AMPs are fusion peptides that consist of a targeting domain of a quorum-sensing signal pheromone from a specific pathogen and a killing domain of a known antimicrobial peptide. The targeting domain can guide such a fusion peptide to bind selectively to the target pathogen, leading to quorum-sensing interference and selective killing. Thereby, pheromone-guided AMPs have added an exciting opportunity to develop new antimicrobials that selectively target pathogens. However, pheromone-guided AMPs and their application as an alternative therapy are still in their infancy. This chapter briefly reviews the current advances in this field.