In vitro activity of AST-120 that suppresses indole signaling in Escherichia coli, which attenuates drug tolerance and virulence

Abstract

AST-120 (Kremezin) is used to treat progressive chronic kidney disease (CKD) by adsorbing uremic toxin precursors produced by gut microbiota, such as indole and phenols. In this study, we propose that AST-120 reduces indole level, consequently suppresses indole effects on induction of drug tolerance and virulence in Escherichia coli including enterohaemorrhagic strains. In experiments, AST-120 adsorbed both indole and tryptophan, a precursor of indole production, and led to decreased expression of acrD and mdtEF which encode drug efflux pumps, and elevated glpT, which encodes a transporter for fosfomycin uptake and increases susceptibility to aztreonam, rhodamine 6G, and fosfomycin. AST-120 also decreased the production of EspB, which contributes to pathogenicity of enterohaemorrhagic E. coli (EHEC). Aztreonam, ciprofloxacin, minocycline, trimethoprim, and sulfamethoxazole were also adsorbed by AST-120. However, fosfomycin, in addition to rifampicin, colistin and amikacin were not adsorbed, thus AST-120 can be used together with these drugs for therapy to treat infections. These results suggest another benefit of AST-120, i.e., that it assists antibacterial chemotherapy.

Adsorption of Phenazines Produced by Pseudomonas aeruginosa Using AST-120 Decreases Pyocyanin-Associated Cytotoxicity

“…It decreases the production of indoxyl sulfate, a uremic toxin derived from indole produced by some kinds of enteric bacteria [ 19 ]. In addition to its role in CKD treatment, we recently found that AST-120 decreased drug tolerance and virulence of E. coli , including enterohaemorrhagic E. coli [ 20 ]. Here, we propose another potential benefit of AST-120 in reducing the cytotoxicity of P. aeruginosa by adsorbing phenazines including pyocyanin.…”

“…In addition to its efficacy in treating CKD, we previously found that indole induced drug tolerance and virulence in Escherichia coli including enterohaemorrhagic E. coli , and AST-120 eliminated these effects by adsorbing indole. Thus, AST-120 reduces drug tolerance and virulence in E. coli [ 20 ]. AST-120 can also adsorb some other small-sized molecules that have aromatic ring structures in addition to indole [ 10 ].…”

Roles of the Tol-Pal system in the Type III secretion system and flagella-mediated virulence in enterohemorrhagic Escherichia coli

“…The gel was electroblotted onto a polyvinylidene fluoride (PVDF) membrane (Bio-Rad Laboratories, Hercules, CA, United States). EspA, EspB and VSVG-tagged FliC were detected with EspA antiserum, EspB antiserum 42 , VSVG antibody (Sigma-Aldrich Co. LLC., St. Louis, MO, United States), an anti-rabbit horseradish peroxidase-conjugated immunoglobulin G (IgG) secondary antibody (Sigma-Aldrich Co.…”

Progress Overview of Bacterial Two-Component Regulatory Systems as Potential Targets for Antimicrobial Chemotherapy

“…This leads to an increase in the antibiotic tolerance in E. coli , including EHEC, and the production of proteins from the type III secretion system, which are required for virulence of EHEC [ 89 , 90 , 91 ]. AST-120 was shown to abolish the effect of indole on the induction of drug tolerance and virulence by adsorbing the indole signal [ 92 ]. This study suggested a potential application of AST-120 in antibacterial chemotherapy.…”

“… ArsR Binding to target DNAs [ 82 ] Flavonoids HsrA Binding to target DNAs [ 85 ] NSC48630, etc. PhoP Binding to target DNAs [ 86 ] E12.1 peptide VanR Binding to target DNAs [ 87 ] Other inhibitors AST-120 - Indole signaling [ 92 ] COM-blockers - CSP activation and export [ 96 ] DADMe-Immucillin As - AI-2 signal generation [ 98 ] …”