Tackling bacterial pathogenesis: a transcriptional regulator as novel target for antivirulence therapy

The lack of antibiotics and the alarming spread of multi-drug resistant (MDR) bacteria is currently leaving clinicians with very limited options to combat infectious diseases as still among the top 10 causes of death worldwide. Innovative strategies to deliver a next generation of drugs are urgently needed, especially those for Gram-negative pathogens. Due to their complex cell envelope characterized by a low permeability barrier and a higher efflux for the presence of several efflux pumps in the outer membrane (OM), Gram-negative bacteria are intrinsically resistant to many antibiotics.
To address the challenge of the discovery of alternative antimicrobials with a new mechanism of action, the aim of my research focuses to inhibit a transcriptional regulator, member of a two-component-system (TCS), involved in the regulation of OM homeostasis by coordination of the expression of porins (outer membrane proteins OMPs). In addition, we show that the transcription factor is implicated in the virulence of Acinetobacter baumannii and of pathogenic Escherichia coli strains. The alteration of the regulator function and the misbalancing of its assembly molecular machines can lead to a compromise in the structural integrity of the bacterial cell layers and ultimately to a reduced strain pathogenicity. The overall aim of the thesis is to explore the role of the transcriptional regulator in virulence and to decipher its directly regulated molecular mechanism underlying its functioning in the high priority A. baumannii pathogen and in the adherent-invasive E.coli clinical isolates. The ultimate goal aims to identify novel chemical entities able to block this transcription factor-mediated gene regulation by interfering with the biosynthesis of the cell envelop and/or by tuning down its virulence factors, disarming the pathogen and rendering it avirulent in the host during an infection. The high degree of the regulator sequence conservation between A. baumannii clinical isolates with Enterobacteriaceae may further provide an opportunity for an innovative anti-virulence discovery in Gram negative therapy, where one compound can be active against multiple threat level pathogens.