Regulatory Mechanisms of the LuxS/AI-2 System and Bacterial Resistance

Abstract

The quorum-sensing (QS) system is an intercellular cell-cell communication mechanism that controls the expression of genes involved in a variety of cellular processes and that plays critical roles in the adaption and survival of bacteria in their environment. The LuxS/AI-2 QS system, which uses AI-2 (autoinducer-2) as a signal molecule, has been identified in both Gram-negative and Gram-positive bacteria. As one of the important global regulatory networks in bacteria, it responds to fluctuations in the numbers of bacteria and regulates the expression of a number of genes, thus affecting cell behavior. We summarize here the known relationships between the LuxS/AI-2 system and drug resistance, discuss the inhibition of LuxS/AI-2 system as an approach to prevent bacterial resistance, and present new strategies for the treatment of drug-resistant pathogens.

Keywords: LuxS/AI-2 system; bacterial resistance; biofilm formation; efflux pump.

FIG 1

Regulation mechanism between LuxS/AI-2 and bacterial resistance. Abbreviations: AI-2 autoinducer-2; LuxS, AI-2 synthase; LrsC, response regulator; MetF, 5,10-methylenetetrahydrofolate reductase; MetE, methionine synthase; MetH, B₁₂-dependent homocysteine-5-methyltetrahydrofolate methyltransferase; THF, tetrahydrofolate; GlyA, serine hydroxymethyltransferase; ThyA, thymidylate synthase; AICAR, 5-aminoimidazole-4-carboxamine ribonucleotide; DHF, dihydrofolate; FolC, dihydrofolate synthase; FolA, dihydrofolate reductase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; Pfs, S-adenosylhomocysteine nucleosidase; SRH, S-ribosylhomocysteine; LuxS, S-ribosylhomocysteinase; DPD, 4,5-dihydroxy-2,3-pentanedione (the precursor of AI-2).

FIG 2

Strategies for QS interception. (1) Signal-generating enzymes (LuxS and Pfs). (2) Signal sequestration and degradation outside the cell. (3) Receptors and transducers in the signal transduction cascade.