Indole Derivatives Obtained from Egyptian Enterobacter sp. Soil Isolates Exhibit Antivirulence Activities against Uropathogenic Proteus mirabilis

Abstract

Proteus mirabilis is a frequent cause of catheter associated urinary tract infections (CAUTIs). Several virulence factors contribute to its pathogenesis, but swarming motility, biofilm formation, and urease activity are considered the hallmarks. The increased prevalence in antibiotic resistance among uropathogens is alarming and requires searching for new treatment alternatives. With this in mind, our study aims to investigate antivirulence activity of indole derivatives against multidrug resistant P. mirabilis isolates. Ethyl acetate (EtOAc) extracts from Enterobacter sp. (rhizobacterium), isolated from Egyptian soil samples were tested for their ability to antagonize the virulence capacity and biofilm activity of P. mirabilis uropathogens. Extracts of two Enterobacter sp. isolates (coded Zch127 and Cbg70) showed the highest antivirulence activities against P. mirabilis. The two promising rhizobacteria Zch127 and Cbg70 were isolated from soil surrounding: Cucurbita pepo (Zucchini) and Brassica oleracea var. capitata L. (Cabbage), respectively. Sub-minimum inhibitory concentrations (Sub-MICs) of the two extracts showed potent antibiofilm activity with significant biofilm reduction of ten P. mirabilis clinical isolates (p-value < 0.05) in a dose-dependent manner. Interestingly, the Zch127 extract showed anti-urease, anti-swarming and anti-swimming activity against the tested strains. Indole derivatives identified represented key components of indole pyruvate, indole acetamide pathways; involved in the synthesis of indole acetic acid. Additional compounds for indole acetonitrile pathway were detected in the Zch127 extract which showed higher antivirulence activity. Accordingly, the findings of the current study model the feasibility of using these extracts as promising antivirulence agent against the P. mirabilis uropathogens and as potential therapy for treatment of urinary tract infections (UTIs).

Staquorsin: A Novel Staphylococcus aureus Agr-Mediated Quorum Sensing Inhibitor Impairing Virulence in vivo Without Notable Resistance Development

“…These results provoked the question, what advantage would staquorsin have over the already described QS inhibitor, savirin. A key feature sought in anti-virulence therapies is their lack of negative impact on the viability of the pathogen, leading to a decrease in the frequency of resistance development ( Rasko and Sperandio, 2010 ; Heras et al, 2015 ; Rampioni et al, 2017 ; Totsika, 2017 ; Fleitas Martinez et al, 2019 ; Amer et al, 2021 ). In the work described by Sully and co-workers, they showed that savirin has no effect on the viability of S. aureus in a concentration up to 6.3 μM, however, upon testing the anti-Agr activity of this compound they routinely used a concentration of 5 μg/ml (13.6 μM) which is more than double the concentration indicated to have no effect on the viability ( Sully et al, 2014 ).…”

“…The " * " indicates a p-value ≤ 0.05, and " * * * " p-value ≤ 0.001. (Rasko and Sperandio, 2010;Heras et al, 2015;Rampioni et al, 2017;Totsika, 2017;Fleitas Martinez et al, 2019;Amer et al, 2021). In the work described by Sully and co-workers, they showed that savirin has no effect on the viability of S. aureus in a concentration up to 6.3 µM, however, upon testing the anti-Agr activity of this compound they routinely used a concentration of 5 µg/ml (13.6 µM) which is more than double the concentration indicated to have no effect on the viability (Sully et al, 2014).…”

Silicone Foley catheters impregnated with microbial indole derivatives inhibit crystalline biofilm formation by Proteus mirabilis

“…The antibiofilm activity of the crude indole extract was tested against strong biofilm forming P. mirabilis isolate P8 (Amer et al, 2021), in addition to the standard strain ATCC 12453. Isolate P8 was recovered from the urine sample of a patient suffering from UTI after obtaining the participant's consent and the approval of the Research Ethics Committee-MSA University.…”

“…Crude indole extract was prepared from a rhizobacterium Enterobacter sp. and coded as Zch127, followed by the identification of composing indole derivatives using LC-MS and HPLC analysis as described in our previous study (Amer et al, 2021). The extract analysis revealed the presence of 9 compounds including tryptophan, 3 methyl indole (skatole), indole-3-carboxylic acid, indole-3-acetic acid, indole-3-lactic acid, indole-3 ethanol, indole-3-pyruvic acid, indole-3 acetaldehyde, indole-3-acetonitrile, indole-3 acetamide.…”

“…The role of indole as an intercellular, interspecies, and interkingdom signaling molecule has drawn the attention to this compound as a possible antivirulence compound (Lee et al, 2015). Several studies have confirmed this hypothesis by reporting the ability of some indole derivatives in inhibiting the virulence activity of many bacteria including Escherichia coli O157:H7, Pseudomonas aeruginosa, P. mirabilis, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus (Lee and Lee, 2010;Lee et al, 2011;Lee et al, 2012a;Lee et al, 2012b;Nikaido et al, 2012;Amer et al, 2021). Thus, the present study aims to evaluate the activity of microbial indole derivatives against the formation of crystalline biofilm by P. mirabilis on the surface of urinary Silicone Foley catheters (SFC).…”