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THE PROJECT
Infectious diseases are a huge burden for global health, being one of the leading death causes worldwide. Bacterial infections account for a significant number of such deaths and the menace becomes even bigger due to the antimicrobial resistance (AMR) threat. The overuse of antibiotics, most of times occurred due to the lack of rapid and precise diagnostic tools, is the main cause for the continuous growth of AMR.
Targeting-QS project aims at the development of rapid, specific and low-cost immunodiagnostic tools through the detection of specific molecules of the bacterial Quorum Sensing (QS) as biomarkers. QS is an intra-communication system that allow bacteria to share information about cell density and regulate several processes as population growth, biofilm formation or pathogenicity. The objective for the developed tools is not only a simple bacteria identification but also a differentiation between infection and colonisation or even a disease progression assessment.
In addition, the project investigates on the potential of antibodies as alternative therapeutic agents, employing it as quenchers to the QS molecules in order to disrupt the cell-to-cell communication and reducing the pathogenicity.
The project is centred in lower-respiratory tract and urinary tract infections and he principal pathogens targeted are Staphylococcus aureus and Pseudomonas aeruginosa, two of the so-called ESKAPE bacteria, considered the most relevant threats for AMR.
The Quorum Sensing machinery of P. aeruginosa is mainly composed by four communication systems (las, rhi, pqs and iqs) which secrete especific signalling molecules (QSsm)that can be used as biomarkers of infection. The detection and quantification of these molecules by immunochemical methods may provide the diagnosis of infections at an early stage more efficiently than conventional techniques, with high detectability and sensitivity. Last but not least, certain QSsm profiles can serve to differentiate between acute and chronic infections or to assess the disease progression. Thus, the combination of immunoassays for different biomarkers could establish a molecular fingerprint associable to different stays of the disease.
The autoinducer peptides (AIPs) are the particular low-weight molecules involved in the Quorum Sensing systems of gram-positive bacteria such as S. aureus. A primary QS system called Agr is responsible for the control of its virulence and allows for a stratification into four different groups (agr I, agr II, agr III and agr IV), each one characterized by the production of a especific AIP. According to literature, there is a clear correlation between the agr type and characteristics like virulence, ability for biofilm formation and AMR profile. Thus, the detection and quantification of AIPs appears as a powerful strategy to provide interesting tools not only for diagnostic purposes but also for phenotype identification and to better understand the pathogenesis of S. aureus.
Interrupting or attenuating the bacterial communication constitutes an attractive approach to develop new therapeutic strategies. This phenomenon, called Quorum Quenching (QQ), relies on the fact that sequestering crucial QS molecules would not only disrupt bacteria communication, but translate on blocking important pathogenic outcomes, toxic or immunomodulatory effects caused by different QS signalling molecules and virulence factors on the host cells. Such quenching may be carried out with monoclonal antibodies, exploiting their ability to bind specifically to the target molecules. Hence, this would not be only a new strategy to treat infectious processes, but indirectly could mitigate the rising of AMR given that bacteria are not killed but its essential properties are disrupted.
