RECYPION aims to investigate a class of complex natural products, collectively referred to as carboxyl polyether ionophores (CPIs), as antibiotics to target resistant bacterial infections. The CPIs have been known for >50 years, but despite numerous studies in the past, its remains unclear exactly how the different members of this class exert their antibiotic potency. It is clear that the CPIs act directly on bacterial membranes. This type of mechanism, however, carries the risk of the compounds also acting on mammalian cells and, as a consequence, having a therapeutic window that is too narrow for development as antibiotics for human use. Paradoxically, a handful of CPIs are employed extensively in the agricultural industry as anti-parasitic agents which demonstrates that the compounds from this class can indeed be safe. The industrially-produced CPIs are a cornerstone of the objectives of RECYPION.
RECYPION aims to leverage the methods of organic chemistry and advanced analytics to widen the therapeutic window of the CPI-antibiotics through preparation of novel derivatives. The project seeks to afford breakthroughs in how compounds from this class can be chemically constructed or modified. Specifically, an approach involving degradation and then reconstruction will be pursued as this allows new variations to be accessed from the abundant, industrially produced, family members. RECYPION also aims to provide fundamental insight into: (1) the behavior of selected polyether ionophores in contact with membranes or other hydrophobic surfaces and (2) their effects on cellular systems. These insights may provide a more clear picture on the different mechanisms of the CPIs which can feed directly back into optimizing the structures for antibiotic activity and selectivity.
The antimicrobial resistance (AMR) crisis, that humanity has unfortunately only just started to experience, will be one of the largest healthcare challenges in the 21st century. No doubt that antibiotics with mechanisms that are not readily subject to resistance development will be needed. The CPIs fit this profile to the point and RECYPION can therefore have an important impact if it can deliver compounds with properties exceeding those of the naturally occurring polyether ionophores. Along this way, RECYPION will attempt to develop methods for breaking down the complex 'polyether backbone' of the CPIs and new methods for constructing them. Although destined for use within the project, these methods may ultimately reach beyond RECYPION and contribute to sustainable protocols for synthesis of complex drug candidates
