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5 Future Possibilities
5.1 Introduction
This is a more speculative chapter aimed at building on ideas and suggested research
directions from the previous chapters. It is not possible to cover all aspects of possible
future directions but particular growth areas have been chosen which indicate, or point
to, new possibilities in the longer term for small molecule designs potentially with
multiple site interactions.
5.2 New Combinations and Single Molecules
with Multi-activity Development Potential
5.2.1 Combinations
A range of alternative possibilities are foreseen in this area investigating new combinations of agents not previously assessed. Much scope also exists for the inclusion of
dual or triple action hybrids in the mix as well as multi-action prodrugs which may
release two antibacterial agents on activation. Dual action single molecules may also
be non-hybridic in design where only one recognition feature is known to interact
with a bacterial target, and the other feature is not known to interact with a bacterial target but from a chemical viewpoint could possibly do so i.e., possibly active
features. Similar considerations could be applied in the prodrug sphere.
For higher order interactions from dual combinations the development and incorporation of new triple action hybrids is indicated. Other agents in the mix could focus
more on indirect complementary actions like efflux pump modulation. Such modulation might be realised through using other known or newly designed efflux pump
inhibitors. With these studies it will be important to engage a range of structural analysis techniques, including cryo-electron microscopy (cryo-EM), to inform and guide
the design of pump inhibitors as well as proposed hybrids incorporating structural
features for interacting with the pumps together with exploring the effects of hybridisation on binding to other bacterial targets. Cryo-EM is likely to be a particularly
powerful technique for such studies especially with the advance to atomic resolution
(Herzik 2020). Cryo-EM was integral to determining the structure of a multidrug
efflux pump from the very problematic bacterial pathogen Acinetobacter baumannii
to a resolution of 2.98 Å (Su et al. 2019). The use of cryo-EM in drug discovery
more generally, including successes as well as limitations and future directions, has
been covered in an incisive review by Renaud et al. (2018). This review includes
a reference to work describing the cryo-EM structure of the Escherichia coli 70S
ribosome in complex with the elongation factor Tu to which the antibiotic kirromycin
is also bound (Fischer et al. 2015). Kirromycin is a potent antibiotic which exerts its
protein synthesis inhibition though binding to the Tu factor.
The cryo-EM technique also helped to uncover the mechanism of action of
the macrocyclic antibiotic fidaxomicin against Mycobacterium tuberculosis (Boyaci
5 Future Possibilities
5.1 Introduction
This is a more speculative chapter aimed at building on ideas and suggested research
directions from the previous chapters. It is not possible to cover all aspects of possible
future directions but particular growth areas have been chosen which indicate, or point
to, new possibilities in the longer term for small molecule designs potentially with
multiple site interactions.
5.2 New Combinations and Single Molecules
with Multi-activity Development Potential
5.2.1 Combinations
A range of alternative possibilities are foreseen in this area investigating new combinations of agents not previously assessed. Much scope also exists for the inclusion of
dual or triple action hybrids in the mix as well as multi-action prodrugs which may
release two antibacterial agents on activation. Dual action single molecules may also
be non-hybridic in design where only one recognition feature is known to interact
with a bacterial target, and the other feature is not known to interact with a bacterial target but from a chemical viewpoint could possibly do so i.e., possibly active
features. Similar considerations could be applied in the prodrug sphere.
For higher order interactions from dual combinations the development and incorporation of new triple action hybrids is indicated. Other agents in the mix could focus
more on indirect complementary actions like efflux pump modulation. Such modulation might be realised through using other known or newly designed efflux pump
inhibitors. With these studies it will be important to engage a range of structural analysis techniques, including cryo-electron microscopy (cryo-EM), to inform and guide
the design of pump inhibitors as well as proposed hybrids incorporating structural
features for interacting with the pumps together with exploring the effects of hybridisation on binding to other bacterial targets. Cryo-EM is likely to be a particularly
powerful technique for such studies especially with the advance to atomic resolution
(Herzik 2020). Cryo-EM was integral to determining the structure of a multidrug
efflux pump from the very problematic bacterial pathogen Acinetobacter baumannii
to a resolution of 2.98 Å (Su et al. 2019). The use of cryo-EM in drug discovery
more generally, including successes as well as limitations and future directions, has
been covered in an incisive review by Renaud et al. (2018). This review includes
a reference to work describing the cryo-EM structure of the Escherichia coli 70S
ribosome in complex with the elongation factor Tu to which the antibiotic kirromycin
is also bound (Fischer et al. 2015). Kirromycin is a potent antibiotic which exerts its
protein synthesis inhibition though binding to the Tu factor.
The cryo-EM technique also helped to uncover the mechanism of action of
the macrocyclic antibiotic fidaxomicin against Mycobacterium tuberculosis (Boyaci