From 10 to 14 July, around 150 researchers gathered at Jacobs University Bremen to discuss novel approaches to fight bacteria. The progress of four European research projects in the field was presented. Following the interesting presentations, collaboration opportunities resulted from this event.
Since the European Commission launched its plan against infectious bacterial diseases, several research projects have been funded. The workshop “Novel approaches to fight bacteria” gathered researchers involved in four of these projects: IMI-ND4BB-Translocation, FORMAMP, NAREB and PneumoNP. Their research goals are to increase the efficiency of antibiotics. They use different approaches to improve the efficiency of antibiotics including new ways to cross the membrane of bacteria. In particular nanotechnology-based approaches are explored.
Understand the defence mechanism of bacteria
Several FORMAMP partners presented at the workshop their current work on studying the interactions between the antimicrobial peptides and the carrier nanoparticles, and the mechanisms behind the antibacterial effect of peptide-loaded nanocarriers. They especially focus on understanding the interaction with biofilms.
D. Bumann (Biozentrum Basel) presented an in depth outer cell wall proteomic approach using Pseudomonas aeruginosa and Acinetobacter baumannii as prominent examples. This work revealed an enormous variation of the outer membrane protein composition in different environmental niches and their correlation with antibiotic resistance. A major bottleneck in the field is to quantify the uptake of small molecules such as antibiotics into bacteria. Mass spectrometry might be one solution but likely requires a separation and accumulation step.
V. Fetz (Braunschweig) reported first results on the use of a sophisticated separation to quantify antibiotic uptake in a bacteria culture. The quality of the separation could be tested using a novel optical approach presented by J.M. Pagès (Aix-Marseille Université) and M. Réfrégiers (Synchrotron SOLEIL). They reported on the possibility to use Synchrotron light source to quantify label free uptake of fluorescent compounds into single bacteria without the need for a separation step.
J. Llop (CIC Biomagune) presenting
New results regarding antibiotic permeability
Towards understanding the role of porins in antibiotic uptake, J. Naismith (University of St. Andrews) and B. van den Berg (Newcastle University) presented an impressive list of recently elucidated high resolution structures of membrane proteins. The availability of high resolution structures provides a starting point for all atom modelling to reveal detailed atomistic features of the antibiotic pathway that indicate potential rate limiting binding/blockages steps (M. Cecarelli, University of Cagliari and U. Kleinekathöfer, Jacobs University Bremen). These data are complemented by new approaches in electrophysiology (M. Winterhalter, Jacobs University Bremen).
Based on available high resolution structural data, all atom modelling can be used now to investigate the interaction between antibiotics and the LPS layer. To this end, W. Im (Kansas University) introduced the state-of-the-art possibilities that he is making now available online. With respect to membrane transporter E. Tajkhorshid (University of Illinois) presented how molecular details can elucidate the function of efflux pumps. H. Zgurskaya (University of Oklahoma) and G. Sandrasegaram (Los Alamos National Lab) made additional highlights from the experimental side. J. Eyermann (University of Cape Town) complemented the talks of the Efflux Pumps session with his perspective on tuberculosis drugs and N. Buddelmeijer (Institut Pasteur Paris) outlined how pathway modifications on bacterial lipoproteins can lead to promising drug targeting strategies.
A special session of Hijacking Bacterial Transport Mechanisms was devoted to the possibility of benefiting from natural uptake systems present in bacteria, in particular siderophores. T. Köhler (Université de Genève) focussed on microbiological aspects and G. Mislin (Université de Strasbourg) discussed the chemistry associated with siderophore-antibiotic conjugates. J. Philippe (Jacobs University Bremen) presented recent attempts to use artificial amino acids as reporters in enzymes to quantify the uptake. Further contribution focussed on the structure of the major efflux transporters of Gram-negative bacteria (M. Pos, Goethe University Frankfurt) or modelling (P. Ruggerone & A. Vargiu, University of Cagliari).
Development of nanotechnology-based drugs
Several formulations in which antibiotics against multidrug resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus retain their antimicrobial activity upon encapsulation were identified within the NAREB consortium. Two of the nanoparticles of the consortium were presented at the workshop as well as results on characterisation of bacterial response to drug-loaded nanoparticles and in vivo imaging of nanoparticles’ biodistribution.
In the FORMAMP project, incorporation of peptide-loaded nanocarriers into functional drug delivery systems for local administration is ongoing. This includes gels and creams to treat skin infections, and aerosols and powders for inhalation to treat lung infections. Stability studies of the formulated AMPs are in progress to evaluate the chemical stability upon storage and the proteolytic stability after administration.
S. Wronski (Fraunhofer ITEM) presenting
Towards in vivo tests and clinical development
The workshop was an occasion to present latest results of PneumoNP tests on the delivery of antibiotic by aerosol. The tested formulations aim to tackle severe lung infections due to Klebsiella pneumoniae. Many aspects of the medication are currently tested: the distribution of the aerosol inside the lungs, the safety of the medication for the body, the added value of formulation, which is based on nano-encapsulated peptides, compared to other treatments.
Importantly, ongoing ex vivo studies evaluate the antibacterial effect of formulated AMPs on infected skin and the biosafety of inhaled nanocarrier systems. Five papers, that exhibit research findings generated by the project FORMAMP, have been published in peer-reviewed international scientific journals during the last months.
Several external speakers enriched the plenary sessions by addressing questions of common interest such as the possible translation of in vitro studies to in vivo. W.J. Weiss (Health Science Center Fort Worth) gave a well-structured in depth overview on the impact of different animal infection models. To complement, P. Warn (Evotec, Manchester) discussed the need to predict the dose based on in vitro studies. As an evening talk, H. Brötz-Oesterhelt (Eberhard Karls Universität Tübingen) gave an overview on antibiotic action on the outer cell wall.
The event was also the occasion to exchange ideas. A full session was devoted to the Marie Curie Innovative Training Network (ITN) students who presented their translocation projects. Also, further collaborations are currently under discussion. In particular, it may be concretised by the exchange of material between PneumoNP and NAREB projects.
This article was written in collaboration with IMI-ND4BB-Translocation, FORMAMP, NAREB and PneumoNP projects. These projects have received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 607694, 604434, 604237, 604182 and IMI115525, and from the EFPIA companies.
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