Extending bicyclomycin treatment of multi-drug resistant Gram-negative pathogens

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Antibiotics have saved millions of lives from infectious diseases and are arguably the greatest medical discovery of the 20th century. Unfortunately, one of the biggest threats to public health in the 21st century is the rise of multi-drug resistant bacterial infections. This rise has been caused by the improper use of antibiotics in medicine and agriculture combined with a shortage in the discovery of new types of antibiotics. This has prompted the World Health Organisation to warn that "with a dearth of new antibiotics coming to market, the need for action to avert a developing global crisis in health care is increasingly urgent", and the UK's Chief Medical Officer, Prof. Dame Sally Davies, to declare that "we are also not developing new drugs fast enough". This is a global problem that requires global action, particularly for the treatment of multi-drug resistant Gram-negative bacterial infections. Gram-negative bacteria are naturally resistant to many antibiotics used clinically, and have evolved to be resistant towards most other antibiotics following years of treatment with those medicines. There are various approaches to tackle this growing problem, including re-purposing "old" antibiotics. These are drugs that were thoroughly tested for efficacy and safety in human clinical trials, but were not then widely used for a variety of reasons. For example, better broad-spectrum alternatives may have been available at the time. The rise of multi-drug resistance means that these molecules may now be very useful, especially because their lack of clinical use means that there has not been an opportunity for resistance to develop in disease-causing bacteria. Additionally, new experiments can sometimes reveal antibacterial activities that were not identified in earlier research. This is the case for bicyclomycin, an old antibiotic that had previously been shown to have moderate bacteriostatic activity towards Gram-negative bacteria. "Bacteriostatic" means that the antibiotic stops bacterial growth, but does not actively kill the bacteria, which can lead to the persistence of an infection. Excitingly, recent work has shown that bicyclomycin can actually kill bacteria ("bactericidal") when it is used alongside another bacteriostatic antibiotic. This unexpected activity makes bicyclomycin a highly promising antibiotic for the treatment of Gram-negative bacterial infections when used in combination with another drug. Therefore, we propose to carry out further work to determine whether bicyclomycin can be widely used in the clinic. This will include testing more accurate models of infection for this novel activity and identifying new compounds that can be used alongside bicyclomycin to stop resistance developing. Bicyclomycin is a molecule that is made naturally by non-pathogenic soil bacteria. Natural products such as this are produced by the action of a series of enzymes (proteins), which are encoded by genes (DNA) in the bacterial genome. Thus, we aim to discover the genes that are responsible for bicyclomycin production. This discovery will allow us to make modifications to the pathway to make more of the compound, which will enable its study in infection models. We can also modify the pathway to produce new versions of bicyclomycin, which might have better activity than the original compound or overcome resistance mechanisms.