Investigating the mechanism of eradication of MDR bacteria by inorganic, organic, and protein-based nanoparticles

Therapeutics

Research Project: 2015-08-01 - 2018-07-31
Total sum awarded: €530 112

The increase in nosocomial infections is adding a substantial burden to the medical system as they result in extended periods of hospitalization. This increase is strongly associated with the emergence of antimicrobial-resistant bacterial strains over the last two decades.The widespread use of antibiotics has resulted in the evolution and spread of these resistant genetic determinants: multidrug resistant (MDR) and extremely drug resistant (XDR) bacteria. There is an urgent need to develope novel antimicrobial agents. kill antibiotic-resistant bacteria. Preliminary results show that inorganic mixed metal and that quorum sensing inhibiting enzyme (QSIE) NPs are effective in biofilm inhibition in pathogenic bacteria. We will investigate why these NPs are effective by studying clinical isolates of MDR bacteria in both planktonic and biofilm forms. The proposed project brings together experts from Israel, Canada, and Spain. Gedanken will sonochemically synthesize and characterize MMO and ANB NPs. Tzanov will synthesize the QSIE NPs, study NP interactions with bacterial membrane models, and together with Banin will evaluate the efficacy of the of NPs against both planktonic and biofilm cultures. Bach will investigate the cytotoxicity and immunological response of the NPs in human cell lines and murine models infected with MDR bacteria, and develop a model of NP antibacterial mechanism using proteomics. Hafeli will perform pharmacokinetic analysis and NP distribution using bioimaging in murine models. The significance of this project is to provide alternative antibacterial agents to tackle an emergent issue in our society.

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  • Aharon Gedanken, Bar-Ilan University, Israel (Coordinator)
  • Horacio Bach, University of British Columbia, Canada (Partner)
  • Tzanko Tzanov, Universitat Politecnica de Catalunya, Spain (Partner)
  • Ehud Barin, Bar-Ilan University, Israel (Observer)
  • Urs Hafelli, University of British Columbia, Canada (Partner)

Outbreaks of infectious diseases caused by pathogenic bacteria and the development of antibiotic resistance urges the development of new antimicrobial agents. Nanomaterials have emerged as novel antimicrobial agents because of their high surface area to volume ratio and the unique chemical and physical properties. It appears that their antimicrobial activity is exerted by a combination of different mechanisms, such as reacting with -SH protein groups, uncoupling respiratory electron transport, changing cell morphology, and causing cell membrane disruption and DNA damage . There are four mechanisms by which bacteria exhibit resistance to antimicrobials: antibiotic inactivation/ modification, alteration of target site, alteration of metabolic pathway, and reduced drug accumulation. None of these mechanisms of resistance have been reported in nanoparticles (NPs) with antibacterial activity. It is thought that the acquisition of bacterial resistance to NPs will only occur if there were multiple protein mutations in a short period of time, which is highly unlikely. Moreover, studies have reported the antibacterial efficiency of NP against multidrug resistant (MDR) bacteria. Biofilm formation constitutes another mechanism that protects bacteria against antibiotics. This protective mode of growth occurs on either living tissues; including lungs, wounds and teeth, or non-living surfaces, such as medical implants and indwelling medical devices. Once formed, biofilms are difficult to remove as they are resistant to biocides and antibiotics when compared to planktonic bacteria. This is thought to be due to the physiological alteration of the bacteria upon attachments to the surface, as well as to cell specialization that may occur within biofilms. Nevertheless, it is crucial to evaluate whether existing or newly developed nanoparticles (NPs) can inflict genetic changes within the bacteria that will ultimately result in resistance. Hence, one of our aims in the consortium was to develop assays that will allow determining the potential of bacteria to develop resistance to NPs developed and synthesized in the project.

Call

2014 - InnovaResistance: Innovative approaches to address antibacterial resistance