4-Quinolones: smart phones of the microbial world.

Abstract

The cellular telephone has revolutionized the way in which humans communicate. Since its invention, this device has evolved into the multifunctional “smart phone”. The smart phone provides us with not only a means of communication but also a useful toolkit for managing our daily lives. For example, the smart phone enables us to check email, take photographs, and get directions, although it remains primarily a communication device. This review will discuss small molecules that serve as bacterial “smart phones”, allowing bacteria to not only communicate but also monitor their external environment. The finding that bacteria communicate to organize group behaviors has revolutionized the way we view these unicellular organisms. The mechanism of bacterial communication was elucidated in the marine bacterium Vibrio fischeri and since has been likened to communication mechanisms used by eukaryotes. Bacterial communication, or quorum sensing (QS), occurs via the sequential production, accumulation, and sensing of small hormone-like molecules, resulting in altered gene expression at defined cell densities. By using QS to regulate gene expression, bacteria coordinate group activities that may be more effective when carried out by a large population. QS is both ecologically and medically relevant. For example, QS controls behaviors as diverse as bioluminescence and virulence factor production (as reviewed in ref 2).1,2 One major group of QS signaling molecules is the heterocyclic 4-quinolone/quinolines (4Qs). 4Qs have been primarily studied in the Gram-negative opportunistic pathogen Pseudomonas aeruginosa. P. aeruginosa produces two primary 4Q QS molecules, 2-heptyl-4(1H)-quinolone (HHQ)3–5 and 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal; PQS; Figure 1).6 In addition to HHQ and PQS, P. aeruginosa produces >50 other 4Qs,3,7 many of which remain functionally uncharacterized. Interestingly, 4Qs produced by P. aeruginosa share the basic 4-quinolone backbone of commercially synthesized quinolone antibiotics8,9 (Figure 1). Indeed, P. aeruginosa produces 4-hydroxy-2-heptylquinoline-N-oxide (HQNO), a 4Q that possesses antibiotic activity,10,11 though its mechanism of action differs from synthetic quinolone antibiotics.12 The purpose of this review is to discuss 4Q-based QS systems, biosynthesis of 4Qs, regulation of 4Q biosynthesis, 4Qs and virulence, and 4Qs in biological roles other than signaling. We will not discuss how 4Qs interact with iron since this topic has been recently reviewed (see refs 13–15). Additionally, since bacterial 4Qs have been recently reviewed (see refs 14 and 16), we will also describe properties of commercial 4Q antibiotics and discuss recent literature that implicates these molecules in signaling.17,18 Finally, we will speculate on new biological roles for 4Qs. This review covers literature published between 1945 and 2009. Open in a separate window Figure 1 Structures of common QS signals and synthetic quinolone antibiotics.