Reducing Environmental Pollution by Antibiotics through Design for Environmental Degradation

Christoph Leder; Morten Suk; Stefanie Lorenz; Tushar Rastogi; Christian Pfeifer; Manfred Kietzmann; Daniel Jonas; Marion Buck; Axel Pahl; Klaus Kümmerer

doi:10.1021/acssuschemeng.1c02243

Reducing Environmental Pollution by Antibiotics through Design for Environmental Degradation

Christoph Leder
, Morten Suk
, Stefanie Lorenz
, Tushar Rastogi
, Christian Pfeifer
, Manfred Kietzmann
, Daniel Jonas
, Marion Buck
, Axel Pahl
, Klaus Kümmerer

Research output: Journal contributions › Journal articles › Research › peer-review

62 Citations (Scopus)

Abstract

The spread of antibiotic-resistant pathogenic bacteria is an increasing health issue worldwide. A possible origin of antibiotic resistance could be the persistence of antibiotics in the aquatic environment. To tackle this problem, restricted control of application of antibiotics in human and veterinary medicine has been proposed. However, these measures do not prevent the spread
of antibiotic resistance but may delay the process, since antibiotics are still continuously emitted into the environment and many persist there. Derived from ciprofloxacin (CIP), CIP-Hemi, a fluoroquinolone with improved environmental properties, was developed following the benign by design approach and using in
silico and in vitro methods. CIP-Hemi was designed to maintain its required metabolic stability (human liver microsomes, intestinal microsomes, blood plasma) and antibiotic activity (MIC in the μg mL−1 range) against the target while transforming into an inactive fragment (CIP-d-CP) and a degradable linker present under acidic conditions, e.g., after excretion or when released into the
environment. Moreover, CIP-Hemi and CIP-d-CP showed weaker cytotoxic and mutagenic or genotoxic effects compared to the parent compound CIP and therefore underline the feasibility of CIP-Hemi as a viable antibiotic drug candidate, demonstrating benign by design as a promising approach.

Original language	English
Journal	ACS Sustainable Chemistry & Engineering
Volume	9
Issue number	28
Pages (from-to)	9358–9368
Number of pages	11
ISSN	2168-0485
DOIs	https://doi.org/10.1021/acssuschemeng.1c02243
Publication status	Published - 19.07.2021

Bibliographical note

Financial support from the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt; Sustainable Pharmacy 2, Project No. 30389) is gratefully acknowledged. The authors thank Steffi Hinz and Janin Westphal for their excellent technical assistance and Lisa Kessler for helpful technical advice on the algal assay. The authors also acknowledge Multicase Inc. and Leadscope Inc. for kindly providing CASE Ultra and Leadscope QSAR software, respectively. A part of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (U.K.) and The University of Queensland (Australia). The molecular structure representations and SMILES codes were generated with Marvin sketch 15.6.8.0 kindly provided by ChemAxon Ltd. (Budapest, Hungary).

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 7 Affordable and Clean Energy
SDG 12 Responsible Consumption and Production

Research areas and keywords

Chemistry
Antibiotics
Benign by design
Fluoroquinolones
Sustainability Science
Sustainable pharmacy
Green chemistry

ASJC Scopus Subject Areas

Chemistry(all)
Chemical Engineering(all)
Renewable Energy, Sustainability and the Environment
Environmental Chemistry

Access to Document

10.1021/acssuschemeng.1c02243

Cite this

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title = "Reducing Environmental Pollution by Antibiotics through Design for Environmental Degradation",

abstract = "The spread of antibiotic-resistant pathogenic bacteria is an increasing health issue worldwide. A possible origin of antibiotic resistance could be the persistence of antibiotics in the aquatic environment. To tackle this problem, restricted control of application of antibiotics in human and veterinary medicine has been proposed. However, these measures do not prevent the spread of antibiotic resistance but may delay the process, since antibiotics are still continuously emitted into the environment and many persist there. Derived from ciprofloxacin (CIP), CIP-Hemi, a fluoroquinolone with improved environmental properties, was developed following the benign by design approach and using in silico and in vitro methods. CIP-Hemi was designed to maintain its required metabolic stability (human liver microsomes, intestinal microsomes, blood plasma) and antibiotic activity (MIC in the μg mL−1 range) against the target while transforming into an inactive fragment (CIP-d-CP) and a degradable linker present under acidic conditions, e.g., after excretion or when released into the environment. Moreover, CIP-Hemi and CIP-d-CP showed weaker cytotoxic and mutagenic or genotoxic effects compared to the parent compound CIP and therefore underline the feasibility of CIP-Hemi as a viable antibiotic drug candidate, demonstrating benign by design as a promising approach. ",

keywords = "Chemistry, Antibiotics, Benign by design, Fluoroquinolones, Sustainability Science, Sustainable pharmacy, Green chemistry",

author = "Christoph Leder and Morten Suk and Stefanie Lorenz and Tushar Rastogi and Christian Pfeifer and Manfred Kietzmann and Daniel Jonas and Marion Buck and Axel Pahl and Klaus K{\"u}mmerer",

note = "Financial support from the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt; Sustainable Pharmacy 2, Project No. 30389) is gratefully acknowledged. The authors thank Steffi Hinz and Janin Westphal for their excellent technical assistance and Lisa Kessler for helpful technical advice on the algal assay. The authors also acknowledge Multicase Inc. and Leadscope Inc. for kindly providing CASE Ultra and Leadscope QSAR software, respectively. A part of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (U.K.) and The University of Queensland (Australia). The molecular structure representations and SMILES codes were generated with Marvin sketch 15.6.8.0 kindly provided by ChemAxon Ltd. (Budapest, Hungary). Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

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doi = "10.1021/acssuschemeng.1c02243",

language = "English",

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T1 - Reducing Environmental Pollution by Antibiotics through Design for Environmental Degradation

AU - Leder, Christoph

AU - Suk, Morten

AU - Lorenz, Stefanie

AU - Rastogi, Tushar

AU - Pfeifer, Christian

AU - Kietzmann, Manfred

AU - Jonas, Daniel

AU - Buck, Marion

AU - Pahl, Axel

AU - Kümmerer, Klaus

N1 - Financial support from the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt; Sustainable Pharmacy 2, Project No. 30389) is gratefully acknowledged. The authors thank Steffi Hinz and Janin Westphal for their excellent technical assistance and Lisa Kessler for helpful technical advice on the algal assay. The authors also acknowledge Multicase Inc. and Leadscope Inc. for kindly providing CASE Ultra and Leadscope QSAR software, respectively. A part of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (U.K.) and The University of Queensland (Australia). The molecular structure representations and SMILES codes were generated with Marvin sketch 15.6.8.0 kindly provided by ChemAxon Ltd. (Budapest, Hungary). Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.

PY - 2021/7/19

Y1 - 2021/7/19

N2 - The spread of antibiotic-resistant pathogenic bacteria is an increasing health issue worldwide. A possible origin of antibiotic resistance could be the persistence of antibiotics in the aquatic environment. To tackle this problem, restricted control of application of antibiotics in human and veterinary medicine has been proposed. However, these measures do not prevent the spread of antibiotic resistance but may delay the process, since antibiotics are still continuously emitted into the environment and many persist there. Derived from ciprofloxacin (CIP), CIP-Hemi, a fluoroquinolone with improved environmental properties, was developed following the benign by design approach and using in silico and in vitro methods. CIP-Hemi was designed to maintain its required metabolic stability (human liver microsomes, intestinal microsomes, blood plasma) and antibiotic activity (MIC in the μg mL−1 range) against the target while transforming into an inactive fragment (CIP-d-CP) and a degradable linker present under acidic conditions, e.g., after excretion or when released into the environment. Moreover, CIP-Hemi and CIP-d-CP showed weaker cytotoxic and mutagenic or genotoxic effects compared to the parent compound CIP and therefore underline the feasibility of CIP-Hemi as a viable antibiotic drug candidate, demonstrating benign by design as a promising approach.

AB - The spread of antibiotic-resistant pathogenic bacteria is an increasing health issue worldwide. A possible origin of antibiotic resistance could be the persistence of antibiotics in the aquatic environment. To tackle this problem, restricted control of application of antibiotics in human and veterinary medicine has been proposed. However, these measures do not prevent the spread of antibiotic resistance but may delay the process, since antibiotics are still continuously emitted into the environment and many persist there. Derived from ciprofloxacin (CIP), CIP-Hemi, a fluoroquinolone with improved environmental properties, was developed following the benign by design approach and using in silico and in vitro methods. CIP-Hemi was designed to maintain its required metabolic stability (human liver microsomes, intestinal microsomes, blood plasma) and antibiotic activity (MIC in the μg mL−1 range) against the target while transforming into an inactive fragment (CIP-d-CP) and a degradable linker present under acidic conditions, e.g., after excretion or when released into the environment. Moreover, CIP-Hemi and CIP-d-CP showed weaker cytotoxic and mutagenic or genotoxic effects compared to the parent compound CIP and therefore underline the feasibility of CIP-Hemi as a viable antibiotic drug candidate, demonstrating benign by design as a promising approach.

KW - Chemistry

KW - Antibiotics

KW - Benign by design

KW - Fluoroquinolones

KW - Sustainability Science

KW - Sustainable pharmacy

KW - Green chemistry

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U2 - 10.1021/acssuschemeng.1c02243

DO - 10.1021/acssuschemeng.1c02243

M3 - Journal articles

SN - 2168-0485

VL - 9

SP - 9358

EP - 9368

JO - ACS Sustainable Chemistry & Engineering

JF - ACS Sustainable Chemistry & Engineering

IS - 28

ER -

Reducing Environmental Pollution by Antibiotics through Design for Environmental Degradation

Abstract

Bibliographical note

UN SDGs

Research areas and keywords

ASJC Scopus Subject Areas

Access to Document

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Cite this