Dissecting the mechanisms underlying molecular accumulation and antibiotic efficacy in single gram-negative bacteria

Dr Stefano Pagliara (Living Systems Institute, University of Exeter) will be giving a talk about his research.

Abstract

Antibiotics play a fundamental role in modern medicine, but drug-resistant pathogens now exist for all known antibiotics. In combination with a major void in antibiotic discovery,[1] this has led to predictions that bacterial infections will cause 10 million premature deaths annually by 2050.[2] From a drug development perspective, the identification of inhibitors of bacterial targets in vitro is relatively straightforward. However, very few of these molecules accumulate at intracellular concentrations capable of inhibiting growth in gram-negative bacteria [3,4] that are therefore intrinsically resistant to treatment with these drugs. This serious bottleneck for antibiotic development is due to the complex cell envelope structure of gram-negatives,[4] which have an asymmetric outer membrane, a periplasm and an inner membrane protecting the cytoplasm where most drug targets are located.

In this talk I will show how using a combined experimental and theoretical approach, based on single-cell microfluidics microscopy and Bayesian inference, respectively, we can unravel the mechanisms allowing individual bacteria to tune their molecular uptake capabilities and understand how we can manipulate the membranes of such bacteria to make antibiotics kill them.[5,6] I will then illustrate our novel single-cell approach to investigate gene expression and response to antibiotics in antibiotic-resistant Escherichia coli and how this led to the identification of candidate biomarkers for isolating these antibiotic surviving subpopulations before drug treatment that we can now use as predictors for the outcome of antibiotic treatment.[7]

References

1. Drive-AB Report Revitalizing the antibiotic pipeline. (2018).  

2. Tackling a Crisis for the Health and Wealth of Nations. Rev. Antimicrob. Resist. (2015).  

3. Nat. Rev. Drug Discov. 6, 29–40 (2007).

4. Curr. Opin. Chem. Biol. 44, 9–15 (2018).  

5. www.biorxiv.org/content/10.1101/645507v2. 

6. Philos. Trans. Royal Soc. B 374, 20180442 (2019). 

7. BMC Biology 15, 121 (2017)

Host: Professor Steve Evans