Interference With Quorum-Sensing Signal Biosynthesis as a Promising Therapeutic Strategy Against Multidrug-Resistant Pathogens

Abstract

Faced with the global health threat of increasing resistance to antibiotics, researchers are exploring interventions that target bacterial virulence factors. Quorum sensing is a particularly attractive target because several bacterial virulence factors are controlled by this mechanism. Furthermore, attacking the quorum-sensing signaling network is less likely to select for resistant strains than using conventional antibiotics. Strategies that focus on the inhibition of quorum-sensing signal production are especially attractive because the enzymes involved are expressed in bacterial cells but are not present in their mammalian counterparts. We review here various approaches that are being taken to interfere with quorum-sensing signal production via the inhibition of autoinducer-2 synthesis, PQS synthesis, peptide autoinducer synthesis, and N-acyl-homoserine lactone synthesis. We expect these approaches will lead to the discovery of new quorum-sensing inhibitors that can help to stem the tide of antibiotic resistance.

Keywords: anti-virulence therapy; antibiotic resistance; quorum sensing; quorum-sensing inhibition; virulence.

Figure 1

Structural comparison between human MTA phosphorylase and E. coli MTA/SAH nucleosidase. (A) Sequence alignment between E. coli MTA/SAH nucleosidase (MTAN; Uniprot ID: A7ZHQ1) and human MTA phosphorylase (MTAN; Uniprot ID: Q13126). (B) Structural alignment between MTAN (green) and MTAP (blue). (C) Active site comparison between MTAN (PDB ID: 1SD1, left) and MTAP (PDB ID: 1NC3, right) with formycin. The structures were retrieved from PDB, and the visualization was done by using Pymol v.1.6.

Figure 2

Interference with S-ribosylhomocysteine lyase (LuxS) activity. (A) S-ribosyl-homocysteine (SRH) ribose ring opening. (B) The opened SRH molecule undergoes aldose-ketose isomerization yielding 2-keto intermediate. (C) The 2-keto intermediate is transformed into 3-keto intermediate via ketose-ketose isomerization. (D) The 3-keto intermediate suffers a β-elimination reaction releasing L-homocysteine and the enol form of DPD. The SRH analog S-(1-Amino-1,4-anhydro-1,5-dideoxy-D-ribitol-5-yl)-L-homocysteine (1) may act as a competitive inhibitor that not suffer ring opening, affecting the aldose-keto isomerization. The 3,5,6-trideoxy-6-fluoro-D-erythro-hex-5-enofuranose (2) may interfere with the formation of the 3-keto intermediate. The S-homoribosyl-L-cysteine inhibitor (3) may interfere with the β-elimination step. The red X indicates inhibition.