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Samenvatting
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Scientists from academia and industry working in relevant multidisciplinary fields in drug discovery, bacterial two-component systems and Gram-negative cell envelope permeability came together to participate in two workshops. The first was on “Anti-virulence strategies based on selective HK inhibition” and the second on “Overcoming the permeability barrier of Gram-negative cell envelopes”. The workshops allowed for some background presentations as well as intensive discussions in small multidisciplinary groups to address key strategic questions relating to the topics of the workshop. We prepared reports on the outcomes of these discussions summarised in an attachment.

The JPI-AMR working group project was advertised on our on our website www.wur.nl/en/project/International-Working-Group-on-Histidine-Kinase-Inhibitors-as-Novel-Anti-infectives-1.htm and via the international JPI-AMR organisation. Additionally, a presentation about HK inhibitors was given at a meeting organised for JPI-AMR funded projects in Paris. Written reviews on “anti-virulence drug strategies” and “overcoming the drug permeability barrier in Gram -negative bacteria” to be published in open access journals (in progress). A small academic-industry network was established which is valuable for future exploitation of intellectual property on new antimicrobials and potential partnerships. The networking activities facilitated new collaboration between people working in different fields leading to two new grant proposals, one of which was funded and the other in second stage of evaluation. We are planning on running another workshop on progress towards anti-virulence drugs for bacterial pathogens later this year (or early 2020) with sponsorship from CARTNET, industry participants and potentially the Dutch National Centre for One Health.

 

Resultaten
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We invited scientists from academia and industry working in relevant multidisciplinary fields, including drug discovery, bacterial two-component systems and Gram-negative cell envelopes to participate in two workshops: (1). Anti-virulence strategies based on selective HK inhibition and (2). Overcoming the permeability barrier of Gram-negative cell envelopes.

 

The first workshop on “Anti-virulence strategies based on selective bacterial histidine kinase inhibition” was organised in Cambridge UK from 25th to 27th September, 2017. The Selective inhibition of target bacterial histidine kinases involved in the regulation of virulence or antimicrobial resistance is a promising strategy with low potential for resistance development and interference with the host microbiome. The workshop focused on molecular basis of selective inhibition and prioritizing targets for selected multi-drug resistant pathogens by taking account of international state-of-the-art research. The purpose was to foster cooperation and collaboration to accelerate progress on developing inhibitors of histidine kinases.

 

Specifically, we aimed to:

• Showcase research on two-component systems (TCS)

• Share ideas on development of bacterial histidine kinase inhibitors (HKIs)

• Prioritize HK targets for bacteria which new antibiotics are urgently needed

• Devise a strategy to increase selectivity of HKIs against histidine kinases involved in virulence and antibiotic resistance.

• Exchange experiences, approaches and lessons learnt

 

The second workshop on “Getting small drug-like molecules into Gram-negative bacteria” was organised in Oxford UK”. It connected the working group and invited experts with the members of the TRANSLOCATION project (http://www.nd4bb.eu), which was funded by the innovative medicines initiative (IMI) antimicrobial resistance (AMR) programme called “New Drugs for Bad Bugs”. TRANSLOCATION was funded to increase the overall understanding of how to get antibiotics into multi-resistant Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae and how to stop the bacteria from ejecting (effluxing) the drug. By sharing knowledge, we aimed to establish best practices for the development of HK inhibitors as novel anti-infective drugs against Gram-negative multi-drug resistant ESKAPE pathogens

 

The aim of the workshop was also to provide a forum for exchanging knowledge on factors influencing uptake and persistence of drug-like compounds into Gram-negative bacteria. The purpose was to foster cooperation and collaboration to accelerate progress on developing

inhibitors of histidine kinases that are active against Gram-negative

pathogens.

 

Specifically, we aimed to:

• Showcase research of the IMI funded TRANSLOCATION project

• Highlight research in development of bacterial histidine kinase inhibitors (HKIs)

• Devise a strategy to increase uptake and persistence of HKIs in Gram-negative bacteria

• Exchange experiences, approaches and lessons learnt

 

 

An extended report including summaries of the recommendations from the workshop discussion groups is provided in as an attachment.

 

 

The main outcomes of the grant were

 

• Written reviews on “anti-virulence drug strategies” and “overcoming the drug permeability barrier in Gram -negative bacteria” to be published in open access journals (still in progress).

 

• The networking activities facilitated interactions between people working in different fields and consequently increased the multidisciplinary nature of ongoing research.

 

• There are now active collaborations between participants who did not collaborate prior to the workshops.

 

• Two grant proposals were strengthened by the trans-national networks, one of which has been funded in an EC ITN network CARTNET involving 6 participants of the workshops. The new project on developing HK inhibitors is multidisciplinary involving chemists, computational chemists, microbiologists/biologists and structural biologists. The second grant proposal on novel antibacterial drugs has been submitted to innovate UK in collaboration with China and passed the first stage of selection.

 

• A small academic-industry network was established which is valuable for future exploitation of intellectual property on new antimicrobials and potential partnerships.

 

• We are planning on running another workshop on progress towards anti-virulence drugs for bacterial pathogens later this year (or early 2020) with sponsorship from CARTNET, industry participants and potentially the Dutch National Centre for One Health.

 

Samenvatting van de aanvraag

Samenvatting
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The objectives of the proposed Working Group are to invite scientists from academia and industry working in relevant multidisciplinary fields, including drug discovery, bacterial two-component systems and Gram-negative cell envelopes to participate in workshops on: (i) Overcoming the permeability barrier of Gram-negative cell envelopes (ii) Anti-virulence strategies based on selective HK inhibition. The workshop will by invitation only and limited to approximately 25 attendees (excluding industrial platform members) so that the discussion and feedback groups at each workshop are not too large to function well and consider all the viewpoints. The Working Group will use their network of industry contacts to establish an industrial platform (InP) with the aim that this industry group can give feedback, advice and help finance future meetings and workshops on anti-infective strategies and antibacterial drug discovery (see Section V).

The anticipated outcomes of the two separate workshops will be documents providing current opinions on these topics (published with open access). Additionally, a summary of each workshop will be published by the Working Group leaders and made available to the participants and the wider scientific community through web-sites of relevant organisations, e.g. the Dutch National centre for One Health. Prospects for collaborative projects will be discussed and funding applications planned. Apart from the strategic value of the workshop to many participants we anticipate that it will strengthen international cooperation and collaboration.

 

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