PharmCycle: a holistic approach to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the environmental risk assessment of antibiotics, and reducing the discharges of antibiotics in the wastewater outlet

Abstract

Background: The overall aim of the interdisciplinary research project "PharmCycle" is to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the environmental risk assessment of antibiotics, and reducing the discharges of antibiotics in the wastewater outlet. An overview of the holistic approach and first results are given. Results: The first step is to design sustainable antibiotics, which are effective against target organisms but, after their use, are less toxic, and are rapidly and completely degradable. To develop sustainable antibiotics, two different approaches (subprojects) are applied within PharmCycle: First, a redesign of the existing antibiotics with chemical and in silico methods ("Benign by Design"). Second, sustainable peptide-based antibiotics are produced with biotechnological methods. In the second step, the environmental risk assessment for antibiotics in the framework of the authorization process and for monitoring purposes is improved. There is a lack of data for the environmental risk assessment of antibiotics on the European market. With more transparency of these data, the environmental risk assessment for active substances and for the class of antibiotics can be improved. The aim is to increase the data availability by applying the Aarhus convention and by providing legal access to environmental information. Beside other shortages in the environmental risk assessment required by the European legislation, the effects of antibiotics directly applied in marine aquacultures are not assessed by marine prokaryotic test systems. Therefore, a marine cyanobacteria test was developed, which is more sensitive to selected priority antibiotics than the marine eukaryotic algae test (DIN EN ISO 10253) required by the European Medicines Agency. Marine cyanobacteria are of high importance for the nitrogen cycle and primary production. Moreover, they seem to play an important role with respect to climate change. To reduce the emission of antibiotics used as human pharmaceutical products to the aquatic environment, the third step focusses on the main pathway, the wastewater. Investigations to improve the wastewater treatment of

Exploring the Specificity of Extracellular Wastewater Peptidases to Improve the Design of Sustainable Peptide-Based Antibiotics

“…[10][11][12] To enable the development of sustainable antibiotics for the benefit of environmental and public health, we believe that new antibiotics should be evaluated for their fate during biological wastewater treatment, along with conventional metrics such as their efficacy, specificity, toxicity, and stability in the human body. 13 Complete inactivation of antibiotics during biological wastewater treatment would protect downstream microbial communities from the selective pressures and stresses caused by antibiotics in the environment. Further, we expect that the rapid inactivation of antibiotics by dissolved extracellular enzymes secreted by wastewater microbial communities would protect the wastewater microbial communities themselves from the selective pressures and stresses caused by antibiotics.…”

“…To enable the development of sustainable antibiotics for the benefit of environmental and public health, we believe that new antibiotics should be evaluated for their fate during biological wastewater treatment, along with conventional metrics such as their efficacy, specificity, toxicity, and stability in the human body . Complete inactivation of antibiotics during biological wastewater treatment would protect downstream microbial communities from the selective pressures and stresses caused by antibiotics in the environment.…”

“…Antimicrobial peptides, such as the recently characterized teixobactin, thanatin, , streptocidin D, albomycin, malacidin, tachyplesin II, and murepavadin, are promising not only because of their specificity for target pathogens ,,, but also for their potential to be rapidly hydrolyzed ( i.e. , inactivated) by extracellular peptidases during biological wastewater treatment. ,, However, previous studies on the biotransformation of antibiotics that contain peptide bonds showed that not all peptide bonds are rapidly hydrolyzed by wastewater peptidases.…”

The accessibility of data on environmental risk assessment of pharmaceuticals: Is the marketing authorisation procedure in conflict with the international right of access to environmental information?

“…The APIs considered were selected, because they are listed on the first [33] and/or second [34] watch list of Water Framework Directive, they have been detected in particularly high concentrations in the environment [2], or they are APIs from the group of antibiotics which were focussed by the project PharmCycle [35] because of the high consumption of antibiotics as human and veterinary pharmaceuticals, their occurrence in aquatic ecosystems [2], and the problem of antibiotic resistance [36].…”

Towards more Sustainable Peptide- based Antibiotics: Stable in Human Blood, Enzymatically Hydrolyzed in Wastewater?

“…[2][3][4] Antibiotics are a class of chemicals for which we and others think that such a strategy should be further investigated. [5][6][7] While there is no doubt that novel antibiotics are needed to successfully fight infectious diseases and that these antibiotics need to be stable in the system where they act on the pathogens (e.g. in human blood in the case of a systemic infection), [8,9] their release into downstream environments should be reduced as much as possible.…”