Liposomal antibiotics to simultaneously enhance antibiotic efficacy and ameliorate systemic inflammation

The World Health Organisation has stated that "antimicrobial resistance (AMR) is an increasingly serious threat to global public health that requires action across all government sectors and society". There is an inexorable rise in AMR globally; by 2050 it is estimated that millions of people will die annually from antibiotic-resistant bacterial infections. Resistant bacterial infections that are not amenable to treatment with currently available antibiotics may progress to sepsis, with resulting increases in mortality and morbidity, and a significant impact on healthcare costs. There is thus an urgent need to develop new strategies to counter AMR. My proposal seeks to address this challenge by developing novel targeted delivery vehicles that selectively bind to bacteria, significantly enhancing the efficacy of existing antibiotics, yet simultaneously reducing toxicity.

Liposomes are very small synthetic spherical structures composed of phospholipids that are similar in many respects to human cell membranes. Liposomes can be modified to achieve specific biochemical properties. They are already used clinically to deliver some drugs but have not been exploited for use against resistant bacteria. We have modified liposomes encapsulating routinely used antibiotics to specifically target bacterial cells. Our preliminary in vitro studies demonstrate a six-fold increase in efficacy against a common pathogen E. Coli, without causing damage to human circulating blood cells, even at concentrations ten-fold greater than concentrations required to prevent bacterial growth. We can also incorporate other anti-bacterial molecules such as antimicrobial peptides and DNA which mimic the action of the patient's own white cells in combatting infection. In addition, a well-recognised side effect of antibiotics is the sudden release of bacterial constituents ('toxins'), triggering an enhanced inflammatory response. We can overcome this problem as liposomes incorporate toxin binders which will neutralise this unwanted effect.

I propose to establish the optimal liposome formulation to enhance efficacy against bacteria yet ensuring safety. I will assess the impact on the potency of different classes of antibiotics and the efficacy against different strains of bacteria, including multi-drug resistant organisms. I will then progress to a range of studies using clinically relevant laboratory models to assesses safety, efficacy and drug handling. This work will hopefully lead to its use in patients.

There is an urgent imperative to develop novel strategies to overcome antimicrobial resistance. An elegant yet underexplored strategy is to enhance the bactericidal efficacy of current antibiotics and this forms the nub of my proposal. Together with my key collaborators, Prof S Howorka and Dr J Burns (UCL Chemistry), we will modify existing antibiotics within a bespoke liposomal shell containing DNA nanotubes. These are designed to trap bacteria within released artificial neutrophil extracellular traps (NETs) and, by utilising positive charge on the liposome membrane, to enhance binding to the high content of negatively-charged lipids on the bacterial cell membrane. The liposome can then fuse to the bacterial outer membrane, allowing direct release of antibiotics into the bacterium. We have exciting pilot data demonstrating that this approach enables a markedly lower in vitro minimum inhibitory concentration. This will be particularly attractive for treating resistant microorganisms but will also enhance killing of sensitive bacteria without needing to increase dose at the expense of toxicity.

A secondary objective is to minimise the inflammatory reaction that occurs with antibiotic-induced bacterial lysis whereupon bacterial cell wall and internal constituents (such as lipopolysaccharide and DNA) are rapidly released, amplifying the host inflammatory response. Neutralisation of toxins will be achieved by incorporating specific lipid components into the bilayer of the antibiotic-containing liposome.

My study aim is to develop this work further, selecting liposome constituents and DNA fibres to achieve optimal efficacy and safety. I am planning initial in vitro studies that will generate lead candidates to be trialled in well-established and clinically relevant rat models of sepsis. This project will generate a wide range of formulations of liposome-encapsulated antibiotics and DNA fibres that will be tested for antibacterial activity and toxicity profile.