Can Bacteria Evolve Resistance to Quorum Sensing Disruption?

Traditional treatment of bacterial infections relies heavily on the use of antibacterial compounds that either kill bacteria (bactericidal) or inhibit their growth (bacteriostatic). Typically, the targets for the main conventional antibiotics are essential cellular processes such as bacterial cell wall biosynthesis, bacterial protein synthesis, and bacterial DNA replication and repair. However, resistance to these drugs arises and spreads very rapidly, even to such an extent that bacteria have been identified that are simultaneously resistant to all available antibiotics 1. The increasing occurrence of resistant bacteria gradually renders antibiotics ineffective in treating infections and has enormous human and economic consequences worldwide. As a result, the identification of novel drug targets and the development of novel therapeutics constitute an important area of current scientific research. An alternative to killing or inhibiting growth of pathogenic bacteria is the specific attenuation of bacterial virulence, which can be attained by targeting key regulatory systems that mediate the expression of virulence factors. One of the target regulatory systems is quorum sensing (QS), or bacterial cell-to-cell communication. QS is a mechanism of gene regulation in which bacteria coordinate the expression of certain genes in response to the presence or absence of small signal molecules (Figure 1). Figure 1 General scheme of a quorum sensing system. Quorum Sensing: Bacterial Cell-to-Cell Communication QS was first discovered in the marine bacterium Vibrio fischeri and was thought to be restricted to only a limited series of species. Later on, similar systems were found to be present in many other Gram-negative bacteria. These Gram-negative bacteria use acylated homoserine lactones (AHLs) as signal molecules (for a review see 2). AHLs are typically produced by a homolog of V. fischeri LuxI and detected by a homolog of V. fischeri LuxR. In addition to the AHL-mediated systems in Gram-negative bacteria, some Gram-positive bacteria also regulate a variety of processes by QS. The QS systems of Streptococcus pneumoniae, Bacillus subtilis, and Staphylococcus aureus, for instance, have been extensively studied (for a review see 3). A different kind of QS system is found in vibrios. These bacteria use multichannel QS systems in which different types of signal molecules are produced. The signal molecules are detected at the cell surface by membrane-bound, two-component receptor proteins that feed a common phosphorylation/dephosphorylation signal transduction cascade (for a review on QS in vibrios, see 4). One of the signals produced by vibrios is the so-called autoinducer 2 (AI-2), a furanosyl borate diester 5. AI-2 activity has been detected in many different species (Gram-negative as well as Gram-positive), although its function as a signal is not generally accepted for all species (for a detailed discussion see 6). The language of bacteria seems to be even more diversified as new QS systems, using different types of signal molecules, are still being discovered 7.