Treatment of multi-drug-resistant Acinetobacter baumannii and Klebsiella pneumonia infections using bacteriophage capsule depolymerases
Biological and Pharmacological Sciences
PI: Prof Peter Taylor (UCL)
Co-PI: Richard Stabler (LSHTM), Nick Thomson (LSHTM/WTSI)
Funding: MRC, 2016-2019
Summary: Acinetobacter baumannii and Klebsiella pneumonia are bacteria with an amazing ability to develop resistance to antibiotics and we are on the verge of having nothing left to treat those infected. We aim to use proteins from viruses that infected the bacteria to disarm it by removing the bacterial protective coat, allowing the human immune system to remove infections.
The rising incidence of antibiotic resistance in Gram-negative bacteria (GNB) poses a serious threat to global health, compounded by the lack of new antibiotics in the drug development pipeline. The ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp) have been identified as primary threats to human health due to antibiotic resistance and acquisition of multi-drug resistance (MDR). Globally, nosocomial spread of MDR ESKAPE pathogens has sharply increased, compounded by travel to endemic areas, facilitating importation into far-removed communities and the environment.
The health burden of antimicrobial resistance in Thailand is severe and is growing. Data for 2010 indicate at least 90,000 hospitalized patients acquired MDR infections, approximately 30,000 of these died and MDR infections resulted in at least 3 million excess days of hospitalization. Between 2004 and 2010 hospitals in northeast Thailand revealed an increase in hospital-acquired bacteraemia from 0.6 to 0.8 per 1,000 patient days, the most common causative agents were Acinetobacter spp (16.2%), K. pneumoniae (13.9%), and S. aureus (13.9%). Around 70% of hospital-acquired and ventilator-associated pneumonia cases were caused by MDR K. pneumoniae, A. baumannii and P. aeruginosa. In general, ciprofloxacin resistance and ESBL producing K. pneumoniae and A. baumannii isolates resistant to most commonly deployed antibiotics, including carbapenems are increasing rapidly and treatment options are increasingly restricted.
The success of A. baumannii and K. pneumoniae as nosocomial pathogens is linked to the production of polysaccharide capsules that provide protection against innate host defences. Despite their relevance to human health, relatively little is known of the nature, diversity and ecology of these pathogens. The project evaluates using an alternative therapeutic strategy based on rapid removal of the capsule on the basis that their removal will facilitate elimination of the invading pathogen from the host. The approach uses bacteriophage, viruses that target bacteria, that use depolymerases to degrade the capsule in order to infect the target host bacteria as part of their normal life cycle. This project aims to determine the capacity of depolymerases, directed against capsule polysaccharides of the most frequently encountered Thai isolates of MDR K. pneumoniae and A. baumannii, to resolve experimental systemic infections. Selection of strains for identification, purification and cloning of depolymerases with appropriate substrate specificity and for establishment of models of infection will be guided by a programme of whole-genome sequencing of recent Thai isolates to identify clades of these emergent pathogens relevant to healthcare in Thailand. Candidate enzymes will be filtered by consideration of key pharmacokinetic parameters in infection models. This approach targets both drug resistance and drug-sensitive strains and is believed to have a lower selective pressure and so less likely to generate resistance.Back