Fast bacterial growth reduces antibiotic accumulation and efficacy

 

This study addresses mechanisms by which bacteria are able to survive and evade killing by antibiotics. Using fluorescent versions of antibiotics it studies whether entry/efflux of the drug itself is a significant contributor to the observed variability of antibiotic activity. This study will be of interest to microbiologists and clinicians for the design of better antibiotic therapies and improves our understanding of the relationships between drug uptake, bacterial growth, and drug efficacy.

Phenotypic variations between individual microbial cells play a key role in the resistance of microbial pathogens to pharmacotherapies. Nevertheless, little is known about cell individuality in antibiotic accumulation. Here, we hypothesise that phenotypic diversification can be driven by fundamental cell-to-cell differences in drug transport rates. 

To test this hypothesis, we employed microfluidics-based single-cell microscopy, libraries of fluorescent antibiotic probes and mathematical modelling. This approach allowed us to rapidly identify phenotypic variants that avoid antibiotic accumulation within populations of Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia, and Staphylococcus aureus. Crucially, we found that fast growing phenotypic variants avoid macrolide accumulation and survive treatment without genetic mutations. These findings are in contrast with the current consensus that cellular dormancy and slow metabolism underlie bacterial survival to antibiotics. 

 

Our results also show that fast growing variants display significantly higher expression of ribosomal promoters before drug treatment compared to slow growing variants. Drug-free active ribosomes facilitate essential cellular processes in these fast-growing variants, including efflux that can reduce macrolide accumulation. We used this new knowledge to eradicate variants that displayed low antibiotic accumulation through the chemical manipulation of their outer membrane inspiring new avenues to overcome current antibiotic treatment failures.

 

See eLife: 

Study title: 'Fast bacterial growth reduces antibiotic accumulation and efficacy'

DOI link to full study: https://doi.org/10.7554/eLife.74062

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)