Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

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.

The world is as close as ever to the emergence of an influenza pandemic caused by an H5N1 influenza virus. This is a deadly bird flu virus and the current strain, known as clade 2.3.4.4b, has now spread across 5 continents, a geographically unprecedented distribution. The virus kills wild birds as well as poultry. The virus also appears to have additional environmental resilience in that it has survived over the summer in regions where bird flu does not normally persist outside of winter. More worryingly, wild mammals that have scavenged dead bird carcasses have been infected, often with fatal consequence. In the UK this includes foxes and otters, in the Americas, sea lions and other marine mammals. So far, only 11 people have been reported infected, but the virus has now found its way into farmed or domesticated animals including farmed mink in Spain, farmed foxes in Finland and cats in Poland. There is much higher and more frequent contact between humans and these animals compared to the wild scavengers or marine mammals, so the likelihood of more human infections, or 'spillovers', from exposure to an animal carrying the virus has increased. At the population level, we are also at risk that this bird flu mutates and gives rise to an epidemic or even a new pandemic. All previous influenza pandemics have originated from viruses that originally circulated in wild birds. Most avian influenza viruses, including this one, cannot immediately cause a new pandemic because they are not adapted for efficient replication in the human airway or for transmission through the air, even if they can infect humans. The pandemic influenza viruses of the last century have sometimes reached humans after infecting and mutating in an intermediate domestic mammal such as pigs. At times like this governments are faced with truly difficult decisions about how much time and money to invest in pandemic preparation for a particular strain. Should we stockpile antivirals and matched vaccines and invest in PPE, or wait and see what develops? In the early 2000s a different strain of H5N1 caused public health concern but never acquired the adaptive mutations to transform into a pandemic virus. Is this one any different? The virus in 2005 killed around 50% of the people it infected during spillover events. Because so few people have been infected as of yet by the current clade 2.3.3.4b H5N1 strain we don't really know how dangerous this virus is for humans and how severe a pandemic would be. To answer these questions, we need to compare the new virus to previous strains, to assess the susceptibility of intermediate animal hosts, and to understand the barriers for this virus to acquire further adaptation to humans at the molecular level. We propose to work as a consortium and take a multipronged approach to risk assess in depth the current clade 2.3.4.4b H5N1 avian influenza viruses for human spillover infection and pandemic potential. The contemporary viruses will be compared with those of the early 2000s, and with other influenza viruses that did cause human pandemics in 1968 and 2009. We will use state of the art approaches to study virus/host molecular interactions, and define how these vary with different isolates of the clade 2.3.4.4b virus and between different host species. We will consider the interactions the virus makes with the human airway from children and adults, to understand who is most likely to be infected by and transmit the virus and who is most at risk of disease. We will incorporate modelling approaches to inform surveillance, asking where and how the virus is most likely to infect mammals that could serve as intermediate hosts. We will develop systems by which mitigations such as antiviral drugs or vaccines could be assessed, if the virus were indeed to jump species.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.