Abstract
Bacterial epiphytes isolated from marine eukaryotes were screened for the production of quorum sensing inhibitory compounds (QSIs). Marine isolate KS8, identified as a Pseudoalteromonas sp., was found to display strong quorum sensing inhibitory (QSI) activity against acyl homoserine lactone (AHL)-based reporter strains Chromobacterium violaceum ATCC 12472 and CV026. KS8 supernatant significantly reduced biofilm biomass during biofilm formation (−63%) and in pre-established, mature P. aeruginosa PAO1 biofilms (−33%). KS8 supernatant also caused a 0.97-log reduction (−89%) and a 2-log reduction (−99%) in PAO1 biofilm viable counts in the biofilm formation assay and the biofilm eradication assay respectively. The crude organic extract of KS8 had a minimum inhibitory concentration (MIC) of 2 mg/mL against PAO1 but no minimum bactericidal concentration (MBC) was observed over the concentration range tested (MBC > 16 mg/mL). Sub-MIC concentrations (1 mg/mL) of KS8 crude organic extract significantly reduced the quorum sensing (QS)-dependent production of both pyoverdin and pyocyanin in P. aeruginosa PAO1 without affecting growth. A combinatorial approach using tobramycin and the crude organic extract at 1 mg/mL against planktonic P. aeruginosa PAO1 was found to increase the efficacy of tobramycin ten-fold, decreasing the MIC from 0.75 to 0.075 µg/mL. These data support the validity of approaches combining conventional antibiotic therapy with non-antibiotic compounds to improve the efficacy of current treatments.
Highlights
The emergence, spread and evolution of antimicrobial resistance (AMR) amongst microorganisms is an ancient biological phenomenon and a direct consequence of the selective pressure imposed by natural selection [1]
26 marine bacterial isolates were screened for the production of quorum sensing inhibitory compounds (QSIs) against the Gram negative acyl homoserine lactone (AHL)-based reporter strains C. violaceum ATCC 12472, and CV026
As the QSI assay using reporter strain CV026 requires exogenous addition of C6-AHL signaling molecule, the results suggest the QSI activity of KS8 observed against the wild type C. violaceum is not attributable to the inactivation of the components involved in the synthesis of the signal molecule
Summary
The emergence, spread and evolution of antimicrobial resistance (AMR) amongst microorganisms is an ancient biological phenomenon and a direct consequence of the selective pressure imposed by natural selection [1]. The expression of AHL lactonase in transgenic tobacco leaves and potatoes significantly enhanced resistance against Erwinia carotovora infections, a pathogen reliant on AHL-mediated quorum-sensing for its virulence [28] Halogenated furanones are another well-characterized class of marine-derived compounds shown to possess QSI activity against a broad range of bacteria [29,30]. The lasI/lasR and rhlI/rhlR QS circuits are based on AHL signaling molecules and regulate 170–400 genes via a complex network [30,46,47] making this pathogen an excellent candidate for the use of antivirulence approaches based on the use of QSIs. The aqueous nature of the marine environment allows the constant development of a ubiquitous microbial biofilm covering the majority of submerged surfaces [48]. A large number of marine natural compounds isolated from a variety of marine organisms possess QSI activity [49] suggesting QS inhibition has evolved as a natural, widespread, antimicrobial strategy with significant impact on biofilm formation, making the marine ecosystems an ideal source for the discovery of QS inhibitors with the potential to increase susceptibility of human pathogens to antibiotics
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