About INNOTARGETS
Antimicrobial resistance (AMR) is a major challenge to human health, and infections due to resistant bacteria are predicted to exceed cancer as the primary cause of human mortality by 2050, and negatively impacting on world economy and social stability.
Introduction, objectives and overview of the research programme
Prudent use of antimicrobials can slow down the development of AMR, but it cannot solve the challenges caused by multi-drug resistant bacteria (MDR), some of which are resistant to all of the current antimicrobials on the market. This requires novel antimicrobials, or drugs that can re-sensitize MDR bacteria to the existing antimicrobials. In accordance with this, the first priority topic in the Strategic Research and Innovation agenda of the Joint Programming Initiative on Antimicrobial Resistance[5], where Europe together with partner-countries coordinates research to solve the AMR crises, is discovery of new antimicrobials and therapeutic alternatives, and the improvement of current antibiotics and treatment regimens.
So far, metabolic enzymes have largely been ignored as targets for antimicrobials, and among the current antimicrobials, only sulfonamides target metabolic pathways. This is due to three knowledge gaps:
- We do not know how pathogenic bacteria modulate metabolic processes during infections, and hence prediction of essential reactions is difficult.
- Metabolic pathways often show redundancy, i.e. more than one pathway can lead to fulfillment of the same end-results, and currently we cannot predict which metabolic enzymes form relevant redundant pairs, and we lack screening approaches to find drugs that can target two redundant enzymes at the same time.
- We lack knowledge on which metabolic enzymes targets we should avoid due to toxicity caused by overlap in metabolic functions between eukaryotic and prokaryotic cells and good methods to predict this.
Due to recent technological advances within omics-technologies, computer modeling and drug screening platforms, we are now in a position, where these knowledge gaps can be closed, thereby significantly increasing the number of putative targets for antimicrobials. INNOTARGET will do this, and combined with state-of-the-art doctoral training, INNOTARGETS also provides research leaders for the future to both industry and academia.
The aim of INNOTARGETS is to train a new generation of early stage researchers (ESRs) in highly innovative approaches to identify metabolic drug targets in pathogenic bacteria. The proposed ETN closes fundamental gaps in European training. We will (i) educate young researchers in approaches to study bacterial metabolism during infection and use of this knowledge in antimicrobial target identification, a critical step to overcoming AMR, and (ii) offer them solid interdisciplinary training in infection microbiology, mathematical modeling and antimicrobial screening techniques. INNOTARGETS’ training equips our ESRs with a holistic view from bench-to-bedside and a creative mind-set with special attention to future clinical/industrial applications of newly developed technologies. This ambitious training program is only possible thanks to a unique consortium with worldwide experts from academic and industrial sectors from six countries, ensuring leading positioning in both the scientific aspects of AMR and target identification, and the inter-sectorial technology transfer onto applications and commercial products and services.
In summary, INNOTARGETS’ mission is to train our ESRs to become the first breed of dedicated experts within antimicrobial discovery with a unique and wide-reaching competence profile, including technical, interpersonal and complementary skill capable of working and collaborating along the continuous spectrum from basic biology to antimicrobial development and across academic and industrial environments. This training will significantly contribute to their employability as the future leaders in the field.
Research in INNOTARGETS is foreseen to result in four different types of novel antimicrobial targets:
- Metabolic enzymes which are essential for bacterial growth in the host, and which can be blocked without affecting host metabolism. Such enzymes can be identified by a number of novel techniques, and INNOTARGETS will train ESRs to utilize the most powerful of these, such as sequence guided transposon technique (TraDis), in situ proteome analysis and metabolic cut-set analysis.
- Metabolic enzymes which are non-essential due to redundancy. Researchers from INNOTARGETS have blocked redundant metabolic enzymes in Salmonella Typhimurium and showed that this attenuated infection. ESRs in INNOTARGETS will develop a model approach to identify pairs of redundant metabolic enzymes, and further develop an approach to systematically identify antimicrobial substances with the ability to block two targets simultaneously, thus making it possible to use redundant targets for antimicrobials.
- Metabolic enzymes, which are non-essential for normal growth, but which become essential when MDR bacteria express their resistance mechanisms. Preliminary research by members of INNOTARGETS consortium have demonstrated that MDR Escherichia coli and Klebsiella pneumoniae respond to treatment with therapeutic concentrations of drugs to which they are highly resistant by adaptive changes in the metabolism, and that blocking some of these adaptations re-sensitized the bacteria to antimicrobials. These observations open a possibility for novel, highly innovative drugs that can potentiate current antimicrobials, and serve to re-sensitize MDR bacteria to drugs that they are currently resistant to.
- Metabolic enzymes which when blocked prevent upregulation of plasmid transfer. Extra-chromosomal elements, termed conjugative plasmids, plays an important role in spread of MDR among bacteria, as plasmids often carry gene cassettes encoding resistance mechanisms and are self-transferable. Research by INNOTARGETS members have surprisingly shown that treatment with some antimicrobials stimulates enhanced spread of resistance carried on plasmids, and they have identified metabolic genes that are essential for the enhanced spread. Blocking of expression of such genes may reduce spread of resistance due to plasmid transfer, and we foresee novel types of drugs, which given together with the antimicrobials, will prevent enhanced spread of resistance.
INNOTARGETS realizes that blocking of antimicrobial targets must not affect the host metabolism. Research by a metabolic model approach into how the metabolism of bacteria and the host affects each other and into methods for in situ prediction of toxicity of hit-molecules are therefor included in the action.
The main goal of INNOTARGETS is to train 12 highly-skilled ESRs – all gaining a doctoral degree – with in-depth knowledge and inter-disciplinary expertise in bacterial metabolism, metabolic modelling, antimicrobial screening approaches, and in situ toxicity evaluation, all critical to development of AMR, complemented with transferable and networking skills, an entrepreneurship mind-set, and first-hand experience of industrial application. This will enable them to become leading scientists and entrepreneurs shaping the future of anti-bacterial drugs. We define 3 research objectives to be addressed in 3 Work Packages (WPs):
- To characterize the in vivo metabolism of Streptococcus suis and Staphylococcus aureus during infection, to identify essential and/or redundant metabolic targets for novel antimicrobials in these organisms, and to develop a screening platform that can identify antimicrobial compounds which can block two targets simultaneously (WP1).
- To improve metabolic and protein model approaches for use in antibiotic target discovery and in prediction of toxicity of lead molecules for antibiotics (WP2).
- To identify metabolic targets that can be blocked to a) re-sensitize MDR S. suis, S. aureus and E. coli to drugs that they are resistant against, or b) prevent spread of resistance by plasmid conjugation (WP3).