The problem: Routine surgery, organ transplantation, stem cell therapy, cancer treatment, and even a simple root canal treatment is inconceivable without effective antibiotics. Antimicrobial resistance poses a major threat to mankind1 and can throw modern medicine back into the dark ages. According to a review presented to the British Government,2 unharnessed antimicrobial resistance will have profound health and macroeconomic consequences for the world, with infections potentially being the major cause of deaths in 2050 and an accumulated cost of 100 trillion Euros in lost output. Under antibiotic pressure, microbes develop multiple strategies for resistance development, ultimately reducing the effectiveness of the treatment. Resistance development has been shown to occur for all antimicrobial agents in clinical use, even for the lastresort drugs. Imperative for future infection control is a more knowledge-based use of antibiotics, where resistance development is taken into account, in combination with the development of new and better drugs.
A constant development of new antibacterial compounds with renewed antimicrobial action is thus one vital element in future infection control. Despite this, no new classes of antimicrobials have entered the clinic the last 30 years. Most antibiotic research has been directed towards small drug-like molecules even though there is little room for addressing truly novel targets within the limited and already thoroughly studied chemical space of small molecules.
The solution: AntiBioSpec moves out of the scientific comfort zone by exploring molecules in the middle space to combat the antimicrobial resistance crisis. Compounds in “middle space” are larger than traditional small molecule drugs but much smaller than biological drugs (e.g. antibodies, enzymes and vaccines). Molecules in middle space has the potential to hit truly unique and largely unexplored targets like bacterial membranes and protein-protein interaction surfaces, opening new antimicrobial modalities that are scarcely utilized by clinically used antibiotics of today. The “middle-space molecules” in use today, e.g. daptomycin and vancomycin, have been shown to possess an inherent resilience to resistance development, but adverse side effects and poor pharmacological properties limits the clinical usefulness. These negative sides are typical challenges in any drug development, but knowledge and methods for addressing these problems in small molecule drugs are well established. “Middle-space molecules” have been largely avoided by the medical industry due to challenging ADMET (absorption, distribution, metabolism, excretion and toxicity) properties and the insufficiency in accurate predictive and descriptive tools, which is the basis for rational drug design. Thus, “middle-space molecules” has precluded the classical design-analyse-improve cycle used by the pharmaceutical industry for this class of molecules resulting in these targets being considered “undruggable”.
AntiBioSpec proposes to discover new antimicrobial “middle-space molecules” by creating the workflows and tools that will move them from the undruggable to the druggable space.
The approach: To successfully achieve the main objective in the realm of novel antimicrobial compounds, we have identified four scientific challenge areas that need to be pursued through frontier research using and extending ”state-of-the-art” enabling technologies, i.e. novel hits, characterization/chirality, membrane interactions/mode of action, pharmacological properties and resistance development. These challenge areas are interconnected and will be addressed in six work packages described below and Figure 1. Access to new molecules is the responsibility of WP1 and WP2. WP1 is a directed biodiscovery effort on a collection of Arctic marine fungi available at MarBio. Fungi are a premier source of antimicrobial cyclic peptides and peptoids, typical examples of “middle-space antibiotics”. WP2 will produce “middle-space molecules” through synthetic methods, complementing the naturally occurring compounds of WP1. WP2 will further interact with WP1 though the production of intermediates that will enable WP1 to produce semisynthetic antimicrobials with enhanced properties. WP2 will also deliver molecules as model compounds for the development and experimental verification of the chiroptical methods that is the objective of WP3. The chiroptical methods will, in addition to the elusive absolute stereochemistry of natural compounds, also describe the conformational space of “middle-space molecules” in their native environment, vital information for improving pharmacological properties of these compounds. WP4 and WP5 are responsible for unraveling the interaction between the active molecules and the microbial membrane, important both as an activity target and as a transport barrier. WP4 will exploit recent advances in NMR based membrane studies using nanodisc technology. This makes it possible for the first time to develop new methods for quantification of membrane disorder and membrane hydration, as well as atomic resolution structural interaction studies of membrane active “middle-space molecules” in their natural environment, i.e. in solution. This will provide highly relevant experimental data for the theoretical modeling of these complex systems. WP5 has the task of describing the membrane “middle-space molecule” interaction through theoretical modeling and will be intimately linked to the experimental results of WP4. The installation of the new supercomputer at UiT will greatly facilitate the use of the “stateof-the-art” methods developed by the Centre for Theoretical and Computational Chemistry (CTCC) in modeling and calculating the properties of “middle-space molecules”. The microbial responses to the active molecules will be handled by WP6. AntiBioSpec will go beyond the “state-of-the-art” by including clinical isolates of target bacterial species in the forced evolution experiments to follow antimicrobial resistance development. Selective pressures across a broad range of concentrations will be used and the molecular mechanisms responsible for reduced susceptibility will be studied. To expand the knowledge, more complex assays to explore the influence of host determinants on the susceptibility and resistance development will be established. Both host-dependent induction of resistance, synergistic effects between antibiotics and host determinants, as well as antagonism between resistance determinants and innate immunity are anticipated. Neither of them is predictable from the “state-of-the-art” in vitro antibiotic susceptibility testing. The results will contribute to future knowledge-based use and development of drugs.