Periodic Reporting for period 1 - LeadtoTreat (Targeted Nano-formulations for Treatment of MRSA: A multicomponent platform for nano-formulated treatment of resistant microbial infections)
Okres sprawozdawczy: 2022-03-01 do 2023-02-28
Many bacteria that cause infectious diseases develop resistance to not only the primary antibiotic treatments available in the clinic but also to drugs of last resort which often require prolonged treatment periods and come with significant side effects. At the same time many promising lead compounds with high activity and wide therapeutic windows have failed to progress to clinical trials due to poor solubility, protein adsorption or other difficulties in formulation (e.g. low drugability). LeadtoTreat proposes a new solution to these challenges by introducing a platform for future infection treatment, enabling targeted delivery of novel lead compounds with low drugability, as well as synergistic combinations of antibiotics and potentiators in a nano-formulation.
The primary objective of LeadtoTreat is to develop a flexible, targeted nanoparticle system for delivery of synergistic antimicrobial treatments, demonstrated with MRSA targeting nano-formulations of difficult-to-formulate-drug leads towards multidrug resistant S. aureus bacterial infections.
This platform technology will be demonstrated by converting a highly active, but water insoluble and protein binding, novel compound into targeted nano-formulations for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections with proven in vivo and in vitro safety. Furthermore, LeadtoTreat aims to identify novel synergistic combinations of antibiotics and potentiators and convert these into highly active targeted nano-formulations for treatment of MRSA infections.
The treatment of bacterial infections on a global scale is facing the enormous challenge of rapidly increasing predominance of antibiotic resistant strains. It is estimated that up to 50,000 lives in Europe and the US and 700,000 lives globally are lost each year due to drug-resistant microbes. These numbers are increasing rapidly, and by 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output are at risk due to the rise of drug-resistant infections. Particularly MRSA infections are a great threat worldwide, especially in hospitalized patients. MRSA colonizes typically in surgical sites, wounds and burns, bone joints, the respiratory system, and implants, and can develop into infection of the central nervous system and in the blood stream (bacteraemia).
The primary objective of LeadtoTreat is to develop a flexible, targeted nanoparticle system for delivery of synergistic antimicrobial treatments, demonstrated with MRSA targeting nano-formulations of difficult-to-formulate-drug leads towards multidrug resistant S. aureus bacterial infections.
This platform technology will be demonstrated by converting a highly active, but water insoluble and protein binding, novel compound into targeted nano-formulations for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections with proven in vivo and in vitro safety. Furthermore, LeadtoTreat aims to identify novel synergistic combinations of antibiotics and potentiators and convert these into highly active targeted nano-formulations for treatment of MRSA infections.
The treatment of bacterial infections on a global scale is facing the enormous challenge of rapidly increasing predominance of antibiotic resistant strains. It is estimated that up to 50,000 lives in Europe and the US and 700,000 lives globally are lost each year due to drug-resistant microbes. These numbers are increasing rapidly, and by 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output are at risk due to the rise of drug-resistant infections. Particularly MRSA infections are a great threat worldwide, especially in hospitalized patients. MRSA colonizes typically in surgical sites, wounds and burns, bone joints, the respiratory system, and implants, and can develop into infection of the central nervous system and in the blood stream (bacteraemia).
The work in the first reporting period of the LeadtoTreat project is progressing according to plan. The focus of the first 12 months period of the project has been to identify suitable antibiotics for encapsulation, to establish in vitro assays with relevant MRSA strains, to perform immunization studies to identify nanobodies for targeting and to develop a first set of antibiotic nano-formulations.
To assess the antimicrobial activity of the LeadtoTreat compounds, a strain panel of S. aureus strains, commercially available and clinical MRSA strains, has been selected, established at the partner sites and characterised at the phenotypic and molecular level. Relevant antibiotics for treatment of MRSA have been identified and based on how suited the antibiotics are for encapsulation in nanoparticles, a panel of compounds has been selected for the initial work in the project. A literature study on potential potentiators has been performed, resulting in a set of compounds to be included in a combinatorial screening with the panel of antibiotics. Susceptibility testing on the entire strain panel have been performed, and combinations of selected antibiotics and potentiators have been tested on subsets of the S. aureus strains. This has led to the identification of synergistic combinations, which will be followed up in the next reporting period.
The consortium partners have established the first antibiotic nano-formulations based on polyphosphazenes as a matrix for nano-formulation. The nano-formulations have been evaluated for in vitro efficacy towards the established MRSA strain panel and a high activity towards MRSA was observed. In the coming period, the work will focus on evaluation and optimization of release kinetics of the nano-formulated antibiotics as well as on development of targeted nano-formulations. The novel nano-formulations will be subject to in vitro studies to characterize the effect towards MRSA as well as in vitro cell based assays to evaluate the cytotoxicity of the formulations
To assess the antimicrobial activity of the LeadtoTreat compounds, a strain panel of S. aureus strains, commercially available and clinical MRSA strains, has been selected, established at the partner sites and characterised at the phenotypic and molecular level. Relevant antibiotics for treatment of MRSA have been identified and based on how suited the antibiotics are for encapsulation in nanoparticles, a panel of compounds has been selected for the initial work in the project. A literature study on potential potentiators has been performed, resulting in a set of compounds to be included in a combinatorial screening with the panel of antibiotics. Susceptibility testing on the entire strain panel have been performed, and combinations of selected antibiotics and potentiators have been tested on subsets of the S. aureus strains. This has led to the identification of synergistic combinations, which will be followed up in the next reporting period.
The consortium partners have established the first antibiotic nano-formulations based on polyphosphazenes as a matrix for nano-formulation. The nano-formulations have been evaluated for in vitro efficacy towards the established MRSA strain panel and a high activity towards MRSA was observed. In the coming period, the work will focus on evaluation and optimization of release kinetics of the nano-formulated antibiotics as well as on development of targeted nano-formulations. The novel nano-formulations will be subject to in vitro studies to characterize the effect towards MRSA as well as in vitro cell based assays to evaluate the cytotoxicity of the formulations
The project has generated data on synergistic effects of combinations of antibiotics as well as potentiators on antibiotic effects towards a large panel of clinically relevant MRSA strains. These results will feed into work focusing on nano-formulation of synergistic drug combinations within the project. The results from the initial combinatorial antibiotic screening may however also have public interest and will be communicated to end users via regular scientific communication channels.
In the coming period will the antibiotic nano-formulations be further developed and optimized regarding in vitro and in vivo efficacy and safety. In the coming period will the project also focus on evaluation of potential means for exploitation of the results. Options will include evaluation of further public funding from national and international funding bodies, e.g. application to EIC Accelerator/Transition or to the OITB PHOENIX. It is the intention of the consortium that the collaboration continues beyond the project to ensure a successful implementation of the results
In the coming period will the antibiotic nano-formulations be further developed and optimized regarding in vitro and in vivo efficacy and safety. In the coming period will the project also focus on evaluation of potential means for exploitation of the results. Options will include evaluation of further public funding from national and international funding bodies, e.g. application to EIC Accelerator/Transition or to the OITB PHOENIX. It is the intention of the consortium that the collaboration continues beyond the project to ensure a successful implementation of the results