AI-2 analogs and antibiotics: a synergistic approach to reduce bacterial biofilms

Abstract

Quorum sensing (QS), the process of autoinducer-mediated cell-cell signaling among bacteria, facilitates biofilm formation, virulence, and many other multicellular phenotypes. QS inhibitors are being investigated as antimicrobials because of their potential to reduce symptoms of infectious disease while slowing the emergence of resistant strains. Autoinducer-2 (AI-2) analogs have been shown to inhibit genotypic QS responses among many bacteria. We demonstrate for the first time, the ability of C1-alkyl AI-2 analog, isobutyl-DPD, to significantly inhibit the maturation of Escherichia coli biofilms grown in vitro. Using a novel microfluidic device that incorporates dynamic, real-time measurements of biofilm density, we also show that a combinatorial approach wherein isobutyl-DPD ((S)-4,5-dihydroxy-2,3-pentanedione) is used with the antibiotic gentamicin is quite effective in rendering near complete clearance of pre-existing E. coli biofilms. Similarly, another AI-2 analog, phenyl-DPD, also used in combination with near MIC levels of gentamicin, resulted in clearance of preformed Pseudomonas aeruginosa biofilms. Clearance of pre-existing biofilms has remained a significant health care challenge; these results warrant consideration of a new approach based on the combination of "quenching" QS signal transduction processes with traditional antibiotic treatment.

Control of Biofilm Formation: Antibiotics and Beyond

“…Interestingly, a clearance of P. aeruginosa biofilm and reduction in pyocyanine production were reported when phenyl-DPD (phenyl-4,5-dihydroxy-2,3-pentanedione), an AI-2 analog, was combined with gentamicin, indicating the possible role of QS systems in biofilm maturation and/or dispersion (84). Furthermore, while lactonase from Bacillus spp.…”

Innovative Strategies for Combating Biofilm-Based Infections

“…Several C1-substituted DPD analogues act as antagonists of AI-2-based QS, with propyl-DPD 19 and butyl-DPD 20 exhibiting IC 50 values ten- fold below that of DPD (Lowery et al 2008 ). Another C1-substituted analogue, isobutyl-DPD 21 signifi cantly inhibits maturation of Escherichia coli biofi lms and also brings about near complete clearance of pre-formed E. coli biofi lms when administered in combination with gentamicin (Roy et al 2013 ).…”

Effect of electrical energy on the efficacy of biofilm treatment using the bioelectric effect

“…29 We tested the effect of the electrical signal energy on the efficacy of the bioelectric effect by applying either a DC field, an AC field or an SP field, in combination with the antibiotic gentamicin to 24-h mature biofilms. Three sets of experiments were performed and the efficacy of treatment was measured: (i) the amplitudes of the three different electrical signals (AC, DC and SP) were chosen such that the magnitude of energy of the SP signal was the sum of the magnitudes of the DC and AC signal energies, (ii) the amplitudes of the AC, DC and SP potentials were chosen such that each signal had the same magnitude of energy when applied over a period of 24 h and (iii) increasing energies of the AC electrical signal was applied over a period of 24 h. The effectiveness of the BE treatment was quantified by the crystal violet (CV) staining method and the live bacterial density results as measured by the colony-forming unit (CFU) assay.…”