Perspectives in Pharmacology Bacterial Communication (“Quorum Sensing”) via Ligands and Receptors: A Novel Pharmacologic Target for the Design of Antibiotic Drugs

The purpose of the present Perspectives is to present a synopsis of the literature on bacterial “quorum sensing” as a background for the proposal that interference with this communication system offers potential targets for the design of novel antibiotic drugs. Quorum sensing is the recently discovered chemical communication system among bacteria (both Grampositive and -negative). It is vital for intraand interbacterial gene regulation and for keeping bacterial colonies (“biofilms”) intact, allowing resident bacteria to assume specialized roles that contribute to enhanced survival of the group. There are several processes involved in quorum sensing that are familiar to pharmacologists; i.e., specific signaling molecules bind to and activate receptors that transduce the quorum-sensing signal into intracellular second messenger responses. We highlight herein the similarity between quorum-sensing communication to ligand-receptor interactions, suggesting that inhibitor drugs could be designed using current standard pharmacologic principles. Such drugs would have novel mechanisms of action and might therefore be more effective against antibiotic-resistant strains of bacteria. When admitted to a hospital, one expects to be treated for the presenting condition, not incur a new one. Yet, every year, an estimated two million people acquire nosocomial infections (Weinstein, 1998) that may be more difficult to treat because many bacteria are resistant to at least one antibiotic and some are resistant to all commonly used antibiotics. For many years, vancomycin provided a last resort against treating resistant Gram-positive infections, but there are now reports of vancomycin-resistant strains (Lowy, 2003). Unfortunately, the development of antibiotic resistance continues to outpace the development of new antibiotics (Walsh, 2003). Multiple factors contribute to resistance, including overuse, infections in immune-compromised patients, and increased use of indwelling medical devices, which provide a fostering environment (Donlan, 2002). The prevalence of biofilms (a strongly adherent assemblage of differentiated microbial cells enclosed in a matrix of polysaccharides) (Stoodley et al., 2002) in infections and on surfaces of medical implant devices has focused attention on the increased antibiotic resistance (1000-fold) of biofilm-resident bacteria versus the more commonly studied planktonic (free-floating) form. It has recently been suggested that biofilm-resident bacteria “communicate” by a process termed quorum sensing and that this contributes to their competitive advantage and enhanced antibiotic resistance. Quorum sensing, which is the detection of the surrounding cell density and activation of appropriate compensatory regulation of cell function, uses chemical signaling and “sensor” molecules. Described in an early review by Fuqua et al. (1994), quorum sensing has subsequently been found to be widespread in Gram-positive and -negative bacteria (Sturme et al., 2002). In this process, compounds diffuse from, or are secreted from, bacteria as the population grows. These compounds—such as -butyrolactones and “auto-inducing peptides” (autoinducers) in GramArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.075150. ABBREVIATIONS: AI-2, N-octanoyl-L-homoserine lactone; AHL/acyl-HSL/HSL, acylated homoserine lactone; AI-1, N-3-oxohexanoyl-L-homoserine lactone; AIP, autoinducing peptide; Lux, luminescence (lux) gene; Lsr, LuxS-regulated. 0022-3565/05/3122-417–423$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 312, No. 2 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 75150/1192061 JPET 312:417–423, 2005 Printed in U.S.A. 417 at A PE T Jornals on M ay 1, 2017 jpet.asjournals.org D ow nladed from positive bacteria and N-acyl homoserine lactones, quinolones, or cyclic dipeptides in Gram-negative bacteria (Hastings and Greenberg, 1999; Dunn and Handelsman, 2002)—diffuse away from the cell and interact with the same or other cells by attaching to and activating specific cell surface-associated or intracellular receptors. Once sufficient signal is detected, transduction leads to the induction of genes that control a variety of survival functions, including the production of antimicrobial substances and protection against the host’s defense mechanisms (Salmond et al., 1995). The recent discovery of an autoinducer produced by the luxS gene found in Gram-positive and -negative bacteria suggests the possibility of “cross-talk” between the two bacteria types (Dunn and Handelsman, 2002). Several organisms seem to have evolved the ability to interrupt this process. Examples include plants (e.g., tomato, rice, and pea) and soil bacteria that secrete compounds that alter homoserine lactone activity and Delisea pulchra, which secretes a halogenated furanone that inhibits quorum-sensing signaling (Bauer and Robinson, 2002). This suggests that synthetic analogs of such substances, or novel compounds from drug discovery efforts, could interrupt quorum sensing in one or more (Stewart, 2003) ways. It is the purpose of this review to highlight the similarity of quorum-sensing processes to ligand-receptor binding and the use of this construct as a guide to direct novel antibiotic drug design efforts based on standard pharmacologic principles and drug discovery processes. The unique nature of their mechanism should provide these new antibiotics with greater activity against currently resistant bacteria.