A widespread bacterial phenazine forms S-conjugates with biogenic thiols and crosslinks proteins

Abstract

Bacterial phenazines react with diverse biogenic thiols and proteins under radical-forming conditions, revealing new biological roles based on conjugation and crosslinking of proteins.

Density-dependent resistance protects Legionella pneumophila from its own antimicrobial metabolite, HGA

“…The catalase experiments presented here have ruled out the production of extracellular H 2 O 2 as a possible mechanism behind HGA inhibition (Figure 3—figure supplement 1B–C). Instead, based on association of lpg1681 and DsbD2 with reduced HGA sensitivity (Figure 5), the ability of diverse thiols to quench HGA’s activity (Figure 3—figure supplement 1E), and precedents from phenazines (Heine et al, 2016), we speculate that HGA’s transient, oxidative intermediates may be toxic by forming adducts on cysteine residues or otherwise disrupting disulfide bonding. Alternatively, HGA-mediated inhibition could occur via the production of other reactive oxygen species, including potentially the generation of intracellular superoxide and/or H 2 O 2 (Hassan and Fridovich, 1979), which would not be affected by catalase treatment.…”

“…HGA-mediated inhibition of Legionella is reminiscent of the antimicrobial activities of phenazines, another class of small aromatic molecules including pyocyanin from Pseudomonas aeruginosa . Both types of molecules are redox-active (Hassan and Fridovich, 1980), are produced at high cell density (Hassan and Fridovich, 1980; Baron et al, 1989), are able to chemically react with thiol groups (Cheluvappa et al, 2008; Heine et al, 2016), and result in the production of a colored pigment (Price-Whelan et al, 2006). Phenazine inhibitory activity is typically thought to come from redox cycling and the production of reactive oxygen species, including H 2 O 2 (Hassan and Fridovich, 1980; Cheluvappa et al, 2008).…”

Synthetic strategies of phenazine derivatives: A review

“…Since then, a plenteous of phenazine derivatives have been synthesized and identified due to their attractive performance [15][16][17][18][19]. According to the documents [20][21][22][23][24][25][26], it was firstly reported in the nineteenth century. Then, the systematically synthetic methodologies about the phenazine derivatives have been advanced in recent years [27][28][29][30][31][32][33][34].…”

Density-dependent resistance protectsLegionella pneumophilafrom its own antimicrobial metabolite, HGA

“…based on association of lpg1681 and DsbD2 with reduced HGA sensitivity ( Figure 5), 563 the ability of diverse thiols to quench HGA's activity (Supplemental Figure 3E), and 564 precedents from phenazines (Heine et al 2016), we propose that HGA (and/or its 565 transient, oxidative intermediates) may be toxic by forming adducts on cysteine residues 566 or otherwise disrupting disulfide bonding. Alternatively, HGA inhibition could occur via 567 the production of other reactive oxygen species, including potentially the generation of 568 intracellular superoxide and/or H 2 O 2 (Hassan and Fridovich 1979), which would not be 569 affected by catalase treatment.…”

“…The strong 546 density-dependence of Legionella's susceptibility to HGA may be another reason that it 547 has been previously undiscovered despite intense study of these bacteria. 548 549 HGA-mediated inhibition of Legionella is reminiscent of the antimicrobial activities 550 of phenazines, another class of small aromatic molecules such as pyocyanin from Fridovich 1980), are produced at high cell density (Hassan and Fridovich 1980;Baron, 553 Terranova, and Rowe 1989), are able to chemically react with thiol groups (Cheluvappa 554 et al 2008;Heine et al 2016), and result in the production of a colored pigment (Price-555…”