The role of the DSB system in antimicrobial resistance
File(s)
Author(s)
Kaderabkova, Nikol
Type
Thesis
Abstract
Extensive use of antibiotics in medicine and agriculture has led to increasing emergence of antimicrobial resistance in bacterial populations. Dwindling resources in the discovery of novel active compound leads and the increasing demands for safety and efficacy of new drugs mean that we are now faced with treatment failures due to multi-drug resistant pathogens. In the quest for new targets that will enable us to counter antibiotic resistance, it is often ignored that many resistance mechanisms precede the clinical use of antibiotics. Instead, the ability to adapt, survive and bypass the toxicity of many chemical compounds is wired within the bacterial genome. Continuous inter-strain and inter-species competition have given microorganisms tools to thrive under conditions of chemical warfare. Recognising this is important when characterising mechanisms underpinning bacterial antimicrobial resistance, as it can lead to novel strategies that can help us bypass it.
The work described here explores the connection between the disulfide bond formation system, a key oxidative protein folding pathway in the cell envelope of Gram-negative bacteria, and two widespread antimicrobial resistance mechanisms, b-lactamase catalysed hydrolysis of b-lactam antibiotics and efflux-mediated drug expulsion. It is demonstrated that oxidative-protein-folding-mediated proteostasis is crucial for both resistance mechanisms, and its inhibition can sensitise multidrug-resistant pathogens to existing antibiotics. Preliminary results from an experimental evolution approach, set the scene for future exploration of the importance of disulfide linkages for the capacity of b-lactamase enzymes to evolve under selective pressure. Together, these findings aim to address the mechanistic basis of a new avenue for antibiotic adjuvant therapy, whereby targeting a non-essential process would allow us to potentiate existing antibiotics towards previously resistant bacterial strains. With novel essential targets against bacteria being scarce, adjuvant approaches like this one could prolong the use and efficacy of existing drugs against some of the most resistant Gram-negative pathogens.
The work described here explores the connection between the disulfide bond formation system, a key oxidative protein folding pathway in the cell envelope of Gram-negative bacteria, and two widespread antimicrobial resistance mechanisms, b-lactamase catalysed hydrolysis of b-lactam antibiotics and efflux-mediated drug expulsion. It is demonstrated that oxidative-protein-folding-mediated proteostasis is crucial for both resistance mechanisms, and its inhibition can sensitise multidrug-resistant pathogens to existing antibiotics. Preliminary results from an experimental evolution approach, set the scene for future exploration of the importance of disulfide linkages for the capacity of b-lactamase enzymes to evolve under selective pressure. Together, these findings aim to address the mechanistic basis of a new avenue for antibiotic adjuvant therapy, whereby targeting a non-essential process would allow us to potentiate existing antibiotics towards previously resistant bacterial strains. With novel essential targets against bacteria being scarce, adjuvant approaches like this one could prolong the use and efficacy of existing drugs against some of the most resistant Gram-negative pathogens.
Version
Open Access
Date Issued
2020-09
Date Awarded
2021-01
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
License URL
Advisor
Mavridou, Despoina
Filloux, Alain
Sponsor
Biotechnology and Biological Sciences Research Council
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)