Characterisation of disulfide bond formation in bacterial pathogens: Unravelling the adaptation of a classical pathway into a virulence aid -

Abstract

Bacteria are fascinating organisms that are able to adapt to a variety of environmental conditions. However, because of this characteristic, bacterial pathogens are able to quickly evolve to bypass human antibacterial measures. The rapid increase in resistance to antibiotics, combined with the slowing to a trickle of new antibiotics progressing through the pipeline over the past decades, could soon lead to a public health crisis.A major reason for antibiotic resistance development is the fact that current antibiotics target components of the bacterial cell which are essential for the viability of the microorganism. This creates selective pressure for the survival of bacteria that are resistant to the antibiotic in use. A way to avoid the emergence of 'superbugs' is to try to render pathogenic bacteria harmless by developing compounds that target their weaponry i.e. the molecules that allow bacteria to invade and damage their host. In this context, we are interested in investigating the option of using a central bacterial pathway, which is involved in the assembly of these weapons, against bacterial pathogens.In bacteria, the Disulfide bond (DSB) protein system is responsible for the formation of additional linkages (called disulfide bonds) in proteins which are located outside the main cellular compartment and need to withstand harsh environments. Since the majority of molecules that promote bacterial virulence are protein based and are also located near the outer surface of the cell, they are dependent on the DSB proteins for correct assembly. Therefore, by studying the DSB protein systems of pathogenic bacteria we will eventually be able to use this knowledge for developing new, efficient ways of neutralising bacterial disease-causing organisms without promoting antibiotic resistance.Our hypothesis is that in bacterial pathogens the DSB pathway has diversified, compared to organisms that are harmless. This allows pathogenic bacteria to optimise their toolkit for invading the host and evading the host's defence mechanisms. Our research strategy relies on a two-prong approach related to this hypothesis. Firstly, we use bioinformatics to determine all variations of the DSB pathway in pathogens and to identify underlying common traits between DSB protein systems of pathogenic bacteria. Moreover, we study experimentally the two most important components of the DSB system (a protein called DsbA, which is essential for the assembly of several bacterial weapons and the protein DsbD which is central for quality control of the folded substrates) in several human pathogens where the DSB pathway has diversified. Overall, we aim to acquire fundamental knowledge about the involvement of this central protein system in bacterial pathogenesis and in-host survival. This knowledge is key for the development of much-needed new antibacterial strategies which will prevent the emergence of antibiotic resistance in the future.