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.
To avoid adverse
side effects of chemicals, pharmaceuticals, and
their transformation products (TPs) in the environment, substances
should be designed to fully mineralize in the environment at their
end-of-life while ensuring a degree of stability as needed for their
application. These considerations should be implemented at the very
beginning of chemical’s and pharmaceutical’s design
(Benign by Design, BbD) to meet requirements set by planetary boundaries
and upcoming legal frameworks (e.g., “Chemicals Strategy for
Sustainability towards a Toxic-Free Environment” by the European
Commission (EC)). In silico tools are already being
implemented in the drug discovery process and the assessment of chemicals
and pharmaceuticals. The advantage of which is avoiding or at least
minimizing animal testing and chemical waste due to experimental testing
as well as reducing the time to market. However, in the literature,
there are just a few examples of how in silico tools
could be implemented in the BbD process. Therefore, this study suggests
a workflow supporting practitioners designing new environmentally
mineralizing chemicals and pharmaceuticals. This would also result
in a much faster and less expensive process than starting with repetitive
synthesis and subsequent experimental testing to improve the compounds’
properties.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.