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3 Single Molecule Non-cleavable Multiply Active Antibacterials
3.1 Introduction to General Design Considerations
An alternative to using combinations of separate compounds is that of a single drug
compound whose structural features intentionally incorporate aspects of the key
recognition elements from some or all of the separate compounds in a combination.
Such hybrid ‘doing-more-for-less’ compounds can be an attractive option in multiplemechanism-based antibacterial design (Silver 2007; East and Silver 2013). In these
compounds the different molecular recognition features are designed to enable interactions with a number of biological target sites. This can be considered as directed
multi-targeting with a single non-cleavable agent rather than a mixture of separate
compounds: one compound, non-cleavable with two or more actions (Decker 2017;
Bolognesi 2019).
There are, however, both advantages and disadvantages with hybrids over combinations. Both approaches are multi-targeting and thus offer the potential advantage
of slowing bacterial resistance development. With a combination, the dosage of each
drug administered can be tailored to the target for optimal inhibition or antagonism,
but with hybrids there is a potential difficulty with specific bacterial target sites being
in different cellular locations, for example if one site is extracellular and the other
intracellular. However with more efficient delivery expected with a single compound
compared with combinations of compounds, it should still be possible to achieve
optimal or greater concentrations at each target to elicit the responses required.
There are, however, significant challenges with regard to conflicting physicochemical property requirements with hybrids in general as noted in the analysis by Morphy
and Rankovic (2006). For multi-action hybrid design it is even more important the
physical distribution of cell components/targets is taken into account and this aspect
is a significant factor in the design process.
A hybrid has different definitions depending on the context. In biology, a hybrid is
a plant or animal that has been produced from two different types of plant or animal
consistent with the Latin meaning of the word (hybrida—a crossbred animal). It
can also be something that is a mixture of two very different things or broadened to
a mixture of two or more things (Cambridge English Dictionary). Thus a mixture
of three or more components in one molecule could still be referred to as a hybrid
(Domalaon et al. 2018). Chemically, resonance hybrid structures may also reflect
input from more than two hypothetical resonance contributing structures. In this
book, though, the word is restricted to inclusion of a mixture of two or more target
recognition features in a single molecule.
3.1.1 General Approaches to Hybrids
General approaches to hybrid design, covering key design points and principles, have
been elaborated in various reviews and book chapters (Dolles and Decker 2017;
Morphy 2012; Simoni et al. 2012; Brötz-Oesterhelt and Brunner 2008). Further
3 Single Molecule Non-cleavable Multiply Active Antibacterials
3.1 Introduction to General Design Considerations
An alternative to using combinations of separate compounds is that of a single drug
compound whose structural features intentionally incorporate aspects of the key
recognition elements from some or all of the separate compounds in a combination.
Such hybrid ‘doing-more-for-less’ compounds can be an attractive option in multiplemechanism-based antibacterial design (Silver 2007; East and Silver 2013). In these
compounds the different molecular recognition features are designed to enable interactions with a number of biological target sites. This can be considered as directed
multi-targeting with a single non-cleavable agent rather than a mixture of separate
compounds: one compound, non-cleavable with two or more actions (Decker 2017;
Bolognesi 2019).
There are, however, both advantages and disadvantages with hybrids over combinations. Both approaches are multi-targeting and thus offer the potential advantage
of slowing bacterial resistance development. With a combination, the dosage of each
drug administered can be tailored to the target for optimal inhibition or antagonism,
but with hybrids there is a potential difficulty with specific bacterial target sites being
in different cellular locations, for example if one site is extracellular and the other
intracellular. However with more efficient delivery expected with a single compound
compared with combinations of compounds, it should still be possible to achieve
optimal or greater concentrations at each target to elicit the responses required.
There are, however, significant challenges with regard to conflicting physicochemical property requirements with hybrids in general as noted in the analysis by Morphy
and Rankovic (2006). For multi-action hybrid design it is even more important the
physical distribution of cell components/targets is taken into account and this aspect
is a significant factor in the design process.
A hybrid has different definitions depending on the context. In biology, a hybrid is
a plant or animal that has been produced from two different types of plant or animal
consistent with the Latin meaning of the word (hybrida—a crossbred animal). It
can also be something that is a mixture of two very different things or broadened to
a mixture of two or more things (Cambridge English Dictionary). Thus a mixture
of three or more components in one molecule could still be referred to as a hybrid
(Domalaon et al. 2018). Chemically, resonance hybrid structures may also reflect
input from more than two hypothetical resonance contributing structures. In this
book, though, the word is restricted to inclusion of a mixture of two or more target
recognition features in a single molecule.
3.1.1 General Approaches to Hybrids
General approaches to hybrid design, covering key design points and principles, have
been elaborated in various reviews and book chapters (Dolles and Decker 2017;
Morphy 2012; Simoni et al. 2012; Brötz-Oesterhelt and Brunner 2008). Further