PhageLive: Development and evaluation of a bacteriophage-live biotherapeutic product combination for targeted gut decolonization
In particularly vulnerable patients, such as those undergoing cancer treatment, colonization of the gut with multidrug-resistant bacteria can increase the risk of severe infections. These include antibiotic-resistant strains of the gut bacterium Escherichia coli. To selectively eliminate such bacteria from the gut, approaches based primarily on antibiotics have been investigated. However, these can disrupt the natural gut microbiota and promote the development of further resistance. The PhageLIVE project is developing a new approach to selectively displace multidrug-resistant bacteria from the gut. To achieve this, bacteriophages, which kill specific bacteria, will be combined with beneficial gut bacteria. The combination is intended to achieve a sustained reduction in unwanted bacteria and thereby reduce patients' risk of infection. The project builds on previous DZIF research and aims to lay the groundwork for the further development of a new therapeutic product.
In high-risk patients, such as those undergoing cancer treatment, colonization of the gut with Escherichia coli (E. coli) producing extended-spectrum beta-lactamases (ESBL) is associated with a high incidence of subsequent infections caused by these pathogens. To reduce the risk of infection in cancer patients, prophylactic strategies for selective digestive decontamination (SDD) that do not further disturb the gut microbiota are being investigated.
To date, the evaluated SDD strategies targeting ESBL-producing Enterobacterales have focused primarily on the use of oral, nonabsorbable antibiotics. However, their use can promote selection pressure and the development of resistance in the gut microbiota.
Combining phages and beneficial gut bacteria
PhageLIVE is pursuing a new approach to targeted gut decolonization: bacteriophages, viruses that can selectively infect and kill bacteria, will be combined with live therapeutic bacteria. These so-called live biotherapeutic products (LBPs) can displace unwanted bacteria by competing for nutrients and space.
Phages are a promising strategy for combating antibiotic-resistant bacteria, as they can rapidly and substantially reduce their numbers. However, phages are highly strain-specific, and previous projects have shown that bacterial resistance to phages can develop rapidly, particularly in the intestinal environment. Conversely, earlier studies of live therapeutic bacteria have shown that LBPs can selectively decolonize unwanted bacteria, although more slowly than phages. They may also help limit the development of resistance to phages.
Laying the groundwork for a new therapeutic product
The project builds on previous DZIF research at University Hospital Cologne (UKK), the Leibniz Institute DSMZ, and the Helmholtz Centre for Infection Research (HZI), particularly the identification of highly active E. coli phages at UKK and DSMZ and the characterization of commensal bacteria with demonstrated potential for targeted gut decolonization of E. coli and multidrug-resistant Enterobacterales at HZI.
The project will now investigate whether the two approaches can be effectively combined to achieve a greater and more sustained reduction in bacterial numbers. The goal is to develop a suitable product candidate that could serve as the basis for future manufacturing under Good Manufacturing Practice (GMP) conditions and subsequent clinical trials.
