Novel antimicrobial agents for bacterial pathogens of livestock: light-activated CO-releasing molecules

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Antimicrobial resistance is a growing problem in the UK and worldwide. We urgently need ways to counteract the effects of the antimicrobial resistance of bacteria in human and animal health. One promising approach is through novel alternatives or additions to antibiotics, so that antibiotics are used less, resistance is countered, and costs are lowered.Carbon monoxide (CO) is a colourless and odourless gas, and an infamous respiratory poison, notorious as the 'silent killer' originating from domestic gas appliances, motor car exhausts and various industrial processes. However, it is also known to be a vital small signaling molecule (or 'gasotransmitter') in microbes, animals and plants. We still know relatively little about how CO gas exerts its many important effects in inflammation, the cardiovascular system and elsewhere. One reason for this is that it is difficult to deliver and manipulate CO doses in biological systems. When CO is applied by inhalation, as is currently being explored in medicine, the final distribution of the gas is difficult to tune, while application to localised sites, e.g. of microbial infection, is virtually impossible. However, because, in small doses, CO has beneficial and essential roles in biology, researchers have started in the last 10 years to evaluate CO-releasing molecules (CORMs) as easy-to-handle, safer and more selective ways to administer CO. Remarkably, these compounds can kill bacteria and the way they work appears entirely different from currently prescribed antibiotics. This proposal focuses on the antimicrobial applications of CORMs in which CO release is triggered on demand by light (PhotoCORMs) so that we can deliver the gas selectively to sites of microbial infection and at chosen times. We aim to understand the antibacterial effects of CORMS in general, and PhotoCORMs in particular, in comparison with more established antimicrobial compounds. In this project we will:a) Develop and synthesise new PhotoCORMs with better biological properties and potential for use as alternatives to antibiotics, or supplements to antibiotics, against bacterial infections. In collaboration with chemists, we will design and make improved molecules in which CO release can be adjusted for particular needs. We will also improve the specific targeting of cells and tissues, again by molecular design;b) Test these compounds for their ability to inhibit the growth or kill bacteria that infect poultry (avian pathogenic E. coli, APEC) by entering the cells and damaging important sites and enzymes;c) Understand how PhotoCORMs get into bacterial cells and whether bacteria take up these compounds more readily than do animal cells;d) Unravel the complex responses that bacteria make when challenged with these compounds and identify perhaps resistance strategies that the bacteria may mount and that could influence future use of PhotoCORMs as antimicrobial agents;e) Exploit this basic knowledge to study how and if these compounds can kill bacteria in in the laboratory, in invertebrate models of pathogenesis in chickens;It is intended that these studies will lead to the future application of CORMs to aid in the battle against antibiotic-resistant infections in animals and man.