Since their discovery in the early 20th century, antibiotics have been used as the primary weapon against bacterial infections. Due to their prophylactic effect, they are also used as part of the cocktail of drugs given to treat complex diseases such as cancer or during surgery, in order to prevent infection. This has resulted in a decrease of mortality from infectious diseases and an increase in life expectancy in the last 100 years. However, as a consequence of administering antibiotics broadly to the population and sometimes misusing them, antibiotic-resistant bacteria have appeared. The emergence of resistant strains is a global health threat to humanity. Highly-resistant bacteria like Staphylococcus aureus (methicillin-resistant) or Enterococcus faecium (vancomycin-resistant) have led to complications in intensive care units, increasing medical costs and putting patient lives at risk. The appearance of these resistant strains together with the difficulty in finding new antimicrobials has alarmed the scientific community. Most of the strategies currently employed to develop new antibiotics point towards novel approaches for drug design based on prodrugs or rational design of new molecules. However, targeting crucial bacterial processes by these means will keep creating evolutionary pressure towards drug resistance. In this review, we discuss antibiotic resistance and new options for antibiotic discovery, focusing in particular on new alternatives aiming to disarm the bacteria or empower the host to avoid disease onset.

A G protein-coupled receptor (GPCR) agonist protein, thaumatin, was site-specifically conjugated at the N- or C-terminus with a fluorophore for visualization of GPCR:agonist interactions. The N-terminus was specifically conjugated using a synthetic 2-pyridinecarboxyaldehyde reagent. The interaction profiles observed for N- and C-terminal conjugates were varied; N-terminal conjugates interacted very weakly with the GPCR of interest, whereas C-terminal conjugates bound to the receptor. These chemical biology tools allow interactions of therapeutic proteins:GPCR to be monitored and visualized. The methodology used for site-specific bioconjugation represents an advance in application of 2-pyridinecarboxyaldehydes for N-terminal specific bioconjugations.

During an infection, pathogens operate by hijacking or promoting crucial intracellular pathways within their hosts. In the case of Enteropathogenic Escherichia coli (EPEC) infection, bacterial proteins interact with host proteins to alter programmed cell death pathways. Recently, it has been found that many proteins from the immune system polymerise to transduce these death signals, forming higher order assembly structures.The aim of this project is to study how EPEC effector proteins interfere with the higher order assembly of immune proteins involved in signal transduction in inflammation, apoptosis and cell survival pathways.A selection of immune system proteins involved in signal transduction in different cell pathways was chosen to perform an in vitro screen against EPEC effector proteins by confocal spectroscopy. It was observed that espF (a bacterial effector protein) was able to change TRAF2 oligomerization/aggregation propensity. TRAF2 is a cytosolic protein involved in signal transduction in the cell death pathway. In cases of infection or stress, the protein forms higher order assembly structures to transduce the signal downstream. Further experiments performed in HeLa cells transfected with TRAF2 showed an increase in these structures in stressed cells when compared with the control group. When espF and TRAF2 were co‐transfected, co‐localization of both proteins was observed in distinct punctate intracellular structures reminiscent of higher order assemblies, together with other changes that are still under investigation.The bacterial protein espF appears to be hijacking the cell death pathway when there is an EPEC infection by avoiding TRAF2 self‐aggregation. Understanding precisely this host‐pathogen interaction could give us information useful for future drug development against EPEC infection.Support or Funding InformationEMBL Australia, University International Postgraduate Award (UIPA), University of New South WalesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.