Bacterial iron uptake pathways as targets for the development of novel antimicrobials

Antimicrobial resistance is an ever increasing problem. Presently it is estimated to be responsible for 700,000 deaths p.a. and it is predicted that this figure will rise to 10 million by 2050. The problem is compounded by the absence of new classes of antibiotics to treat bacterial infections during the past few decades. Therefore, new strategies to combat bacterial infections are required. Many bacteria that exhibit resistance to a wide range of antimicrobial compounds show very low uptake of the antibiotic across the cell envelope either due to a low permeability to the antibiotic or the presence of an efficient efflux system that rapidly removes it from the cell. One approach to promote the uptake of antimicrobials is to design so-called ‘Trojan horse’ antimicrobials. In this approach, an antimicrobial compound is tethered to a molecule that is efficiently transported into the bacterium, thus ‘tricking’ the bacterium into actively importing the antibiotic.

Gram-negative bacteria contain an outer membrane in which are embedded transport proteins known as TonB-dependent transporters (TBDTs). Each TBDT is specific for a particular compound or group of closely related compounds which are then transported across the outer membrane in an energy dependent manner. These compounds include metal chelates such as haem, vitamin B12 and iron-siderophore complexes (siderophores are compounds secreted by bacteria that bind iron with high efficiency and facilitate the uptake of iron into the cell).

It has been shown that some antibiotics that are conjugated to siderophores can be efficiently internalised by bacteria via the specific TBDT for the siderophore, and thereby result in killing of the bacterium, i.e. they act as Trojan horse antimicrobials. As a prerequisite for designing siderophore-based antimicrobials that are active against particular Gram-negative bacterial pathogens, it is necessary to identify siderophores that can be utilised by these species. Thus, one aim of the project is the identification of siderophores that can be utilised by specific bacterial pathogens. We will also identify the TBDTs responsible for the uptake of such siderophores. We will also elucidate the function of TBDTs that are involved in transporting other nutrients across the outer membrane.