Fighting AMR of hard-to-reach microbial pathogens by repurposing antibiotics using a targeted liposomal delivery strategy: A Helicobacter pilot study

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Background: Antimicrobial resistance (AMR) is a major threat to global health, particularly in low-income countries, where access to antibiotics is less restricted, leading to frequent overuse. This in turn leads to increasing failure of previously efficacious antibiotics to eradicate infection. H. pylori (Hp) is a bacterium infecting 80% of adults and 70% of children In Vietnam. In comparison, prevalence is <15% in many parts of the UK. The increasing prevalence of AMR strains is the crucial cause for failure in controlling Hp, leading to higher medical costs, and increased mortality and morbidity from related diseases. A 2015 study in Vietnam found 42.4% strains resistant to clarithromycin, 41.3% to levofloxacin, and 76.1% to metronidazole. ODA compliance: Hp is the main cause of gastrointestinal ulcers and stomach cancer. The high prevalence of disease and a high rate of reinfection in Vietnam is thought to depend on the low socioeconomic status, e.g. crowded living and poor hygienic conditions. There is now a huge discrepancy between low income and affluent countries in terms of Hp prevalence and related diseases, such as gastric cancer. The latter is the 4th most common type of cancer in Vietnam, but only the 16th in the UK. The impact of Hp is particularly strong on the more vulnerable sections of the population; cancer (e.g. gastric cancer caused by Hp) is a significant cause of impoverishment associated with the costs of its treatment in vulnerable sections of the Vietnamese population, pushing many households into poverty. Therefore, our project, which is designed to train Vietnamese scientists and clinicians in cutting-edge advanced drug delivery, empowering the Vietnamese health system to develop and ultimately make available this new treatment to the general population. Hence it is likely to lead to long term socioeconomic benefits to poorer sections of the Vietnamese population, in line with official development assistance principles.One cause underlying the failure of antimicrobial treatment to eradicate Hp infection is the low accessibility of the drug to the bacterium, underneath the thick mucus and in crypts. Further factors are the short retention times of drugs in the stomach, and the susceptibility of some antibiotics to stomach acid. As a result, some antibiotics which are highly effective against Hp in vitro have failed in vivo. Solving these two problems, by increasing the gastric retention time and protecting the antibiotics from the stomach acid, would increase efficacy of treatment in eradicating Hp infection while allowing the use of existing antibiotics which currently cannot be used. Repurposing of antibiotics is a very cost-effective strategy to fast-track the drug development process. Our long term aim is to contribute to improve the health of the population in Vietnam by reducing the prevalence of GI ulcers and gastric cancer. We suggest solving the problem of short gastric retention times and gastric acid inactivation by using functionalized liposomes. These will adhere to the gastric epithelium and mucus due to the addition of two Hp adhesins (BabA and LabA) on their surface. The increased gastric retention of drugs encapsulated in the functionalized liposomes will be verified in vivo using NanoSPECT-CT imaging, which we have successfully tested in mice. Binding of functionalized liposomes to epithelial cells will be assessed in vitro by measuring binding to human gastric cell line AGS stably transfected with human MUC5AC, a mucin which contains the physiological ligands of BabA and LabA used for liposome functionalization. Screening of ~600 clinical Hp isolates from both the UK and Vietnam will allow us to identify various levels of AMR and allow us to test the efficacy and safety (e.g. cell toxicity) of our functionalized liposomes in vitro. Finally, the ability of this formulation to eradicate Hp will be assessed in vivo using am established murine infection model.