Developing a new class of antibiotics based on efflux resistant 4-oxoquinolizines for multidrug-resistant ESKAPE pathogens

Antibiotics have been a mainstay of modern medicine of the last 60 years and have been the principle means of treating infections. Although not a new problem, there is increasing evidence that antibiotics are becoming less effective in certain settings, due to the emergence of bacteria which are no longer susceptible to treatment with antibiotics. This is defined as antibiotic / antimicrobial resistance, AMR. In recent years there has been a rapid rise in bacteria which are resistant to multiple antibiotics, leading in some cases, to essentially untreatable infections associated with high mortality. These so-called multidrug resistant (MDR) bacteria come from a variety of different species and are a major cause for concern. There are a wide range of documents which aim to define this phenomenon, understand what impact it will have on public health worldwide, estimate the likely costs of AMR and identify solutions to the problem. These include research strategy documents from the Department of Health and Social Care, a review of AMR commissioned by the UK government (the AMR Review chaired by Lord O'Neil) and recent documents from the World Health Organisation, European Union, and Centres for Disease Control in the US.

A common feature in AMR is the ability of bacteria to increase the presence or abundance of certain proteins which are able to pump an antibiotic out of the bacterial cell, which stops them working. These so-called "efflux pumps" are common and can work on many different types of antibiotic. Although an attractive approach would be block these pumps to stop them working, using efflux-pump inhibitors (EPIs), this has proved to be difficult to achieve. This is at least partly due to the toxicity of some of the drugs that have been tried in this context.

The project team have developed a new approach which uses state of the art computational methods to identify where and how different molecules bind to the efflux pumps. The team identified that inhibitors bind to specific parts of the pump which are different from antibiotics that may be exported through the pump. This has led to a new approach, where hybrid molecules are made, which keep the active part of the antibiotic and add on specific parts of the inhibitor molecule. This means the modified antibiotics can no longer be exported from the cell, which makes them work better. This approach is applied here to a new class of antibiotics that have not been used in the clinic previously and this potentially allows us to bring a new class of antibiotics into clinical use. We will focus on a high priority group of bacteria, which were identified previously by WHO as those most urgently needing new antibiotics. These bacteria are associated with lung infections, especially in hospital environments, and patients who are infected may have very poor outcomes with current treatment.

Although focussed on a very specific class of new antibiotics, the method can be used with other types of antibiotic and we have already proved this in the laboratory. This means that findings from this study may be useful for other drug developers and may contribute to improved approaches for antibiotic development.

Antimicrobial resistance (AMR) is a major concern, with increased levels of multidrug resistance (MDR) in many pathogens, resulting in treatment breakdown in the clinic. The O'Neil report suggested that infections caused by antibiotic resistant bacteria could become the leading cause of mortality worldwide, with up to 10 million deaths per year by 2050. The situation is exacerbated by the very poor pipeline of new antibiotics, especially in the case of high priority pathogens identified as being of critical concern by WHO and others.

In many Gram-negative bacteria, efflux pumps play a significant role in resistance to antibiotics and, simultaneously, the ability of bacteria to develop stable high level resistance through target site modifications. Although the development of stand-alone efflux pump inhibitors, which can be used in conjunction with antibiotics to suppress this response, is an attractive idea, it has not been possible to advance candidates to the clinic. We have taken a different approach, by identifying differential binding sites of inhibitors and substrates to efflux pumps, and generating hybrid molecules where efflux-resistance is a feature of the molecule. Such efflux resistance breaker (ERB) modified antibiotics have significant potential for therapeutic development as stand alone therapies and/or as part of a combination therapy. We have good evidence that these compounds are effective against Acinetobacter baumannii, and the medicinal chemistry optimisation and validation of the technology will extend the utility to other WHO priority pathogens, for which new antibiotics are urgently required. Data generated in this project will provide a framework for the development of efflux-resistant antibiotics, which are potentially more robust in clinical use. The project will focus on lung infection as the primary indication, aiming to [provide early data to support development of new treatments for hospital and ventilator-associated pneumonia.