Systems biology approach for targeted control of antibiotic-tolerant biofilm sub-populations
A team of researchers from the Singapore Centre for Environmental Life Sciences Engineering (SCELSE) have used a novel proteomic strategy to elucidate pathogen-related biofilm physiology and develop treatments that directly target antibiotic-tolerant subpopulations, in a bid to alleviate the problem of antibiotic resistance. Their work was recently published in Nature Communications(1).
Biofilms cells are physiologically heterogeneous in nature, whether they exist as populations or multi-species consortia. Such variability, together with matrix properties, fosters resistance to environmental stressors such as antimicrobials and host immunity. It therefore stands to reason that a targeted approach founded in understanding the physiological properties of biofilms is valuable for combatting the escalating problem of antibiotic resistance.
Such an approach taken by a team of researchers in Singapore has produced a novel and promising strategy that employs proteomics to simultaneously characterise the physiologies of sensitive and antibiotic-tolerant subpopulations in biofilms.
Members of the Singapore Centre for Environmental Life Sciences Engineering (SCELSE) 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 hours of 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 labelling 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 micro-colonies 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 micro-colonies, 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 micro-colonies by combining colistin treatment with a drug that targets both the migration mode and QS signalling in P. aeruginosa. Developing technologies that successfully control harmful biofilms requires an detailed understanding of the biofilm mode of microbial life. Although approaches to such questions have historically been constrained technologically, advances such as those utilised by the authors have enabled the use of a systems biology approach for elucidating biofilm-related disease and improving treatment/therapeutic strategies.
The novelty here is in 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. Given that natural biofilms are highly complex, such an approach could prove promising for teasing out the intricate interactions associated with biofilm physiology.
1. Chua et al. (2016) Selective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms. Nature Communications 7: 10750.