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Systems biology approach for targeted control of antibiotic-tolerant biofilm sub-populations
19 February 2016

SCELSE researchers have used a novel proteomic strategy to elucidate pathogen-related biofilm physiology for developing treatments that directly target antibiotic-tolerant subpopulations. The targeted approach is grounded in understanding the physiological properties of biofilms and is valuable for combatting the escalating problem of antibiotic resistance.This novel and promising strategy employs proteomics to simultaneously characterise the physiologies of sensitive and antibiotic-tolerant subpopulations in biofilms.

The SCELSE researchers and collaborators investigated subpopulations of the pathogen Pseudomonas aeruginosa after exposure to colistin (considered a ‘last-resort’ antibiotic). They found that colistin tolerance was developed within 24 h exposure when grown as a biofilm, despite being highly susceptible when living in the planktonic mode. Such findings are not new, but using a novel proteomic strategy (pulsed-stable isotope labeling with amino acids; pulsed-SILAC) to quantify newly expressed proteins in the resistant subpopulation, the authors determined that the drug-tolerant cells migrated to the top of the dead microcolonies in a coordinated process using type IV pili. Further, the colistin-tolerant cells were found to employ quorum sensing (QS) to initiate formation of new colistin-tolerant microcolonies, highlighting the importance of social behaviour in antibiotic tolerance development.

Based on these mechanistic findings, the authors devised a novel treatment strategy that significantly represses the development of colistin-tolerant microcolonies by combining colistin treatment with a drug that targets both the migration mode and QS signalling iP. aeruginosa.

The novelty in this study lies with the application of pulsed-SILAC to coexisting subpopulations within the same biofilm (it has previously been used to compare discrete biofilm and planktonic cells), to determine the abundance of new proteins from antibiotic-sensitive and -tolerant cells. This opens up the prospect of understanding bacterial responses to similar stressors in many systems and, accordingly, devising appropriate targeted therapeutic approaches.

Image: The migration and formation of colistin-tolerant subpopulations in biofilm. P. aeruginosa PAO1 wild-type biofilms treated with colistin. Colistin-tolerant cells in the biofilm migrated onto the dead biofilm, forming a live colistin-tolerant biofilm. Live cells are green, dead cells are red or yellow (Chua et al. (2016)).

 
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Chua et al. (2016) Selective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms. Nature Communications 7: 10750.