3.3 Triple Action Antibacterial Hybrid Agents
107
extract needs to done, tetrahydroamentoflavone is one of the significant components
in the active extract, and it is thus conceivable that incorporating elements of this
flavonoid structure in the hypothetical structure (Fig. 3.33a) might also show quorum
quenching activity. With such a compound there could thus be a DNA focus for two of
the interactions (A/B portion) while C might interfere with the NorA pump-mediated
efflux of the molecule in Staphylococcus aureus. Indicative assessment of the NorA
pump inhibitory activity would have merit in this process in order to highlight the
most likely designs to be of interest. Such assessments might usefully involve in silico
docking studies on a homology model of the pump for which an X-ray structure is
not currently available (Gupta et al. 2018; Zimmermann et al. 2019).
On a general note, other groupings of target recognition elements can be envisaged
which are not covered by types i–vi but which would extend the possible design
possibilities for future studies. By way of illustration, one could for example consider
structural types involving just two recognition elements, A and B, but with one having
two different binding sites and the second a different site for the triple activity. The
units A and B might then be linked by one or more extra linking atoms (A---B) or be
directly linked or fused or be linked by a common atom (AB). Further progression
of the fusion would then lead to condensed systems represented by A/B.
3.4 More Than Triple Action Hybrid Agents
One would be justified in asking whether incorporation of more than three separate
recognition sites in the one hybrid molecule was a pipedream or was it a likely
possibility for multi-modal single molecule antibacterials? This author considers
that it is likely to be the latter on the basis of such intentionally designed agents
with potentially more than three separate activities in other areas being described, for
example, in the development of new antipsychotic drugs (Zajdel et al. 2018). Hybrids
were deliberately designed for interactions with greater than three receptor or receptor
sub-type sites and included structural elements known to favour selective interactions
with monoaminergic receptors; both agonistic and antagonistic interactions were
observed depending on the receptor, together with SERT blockade in a selected
instance.
But there are inherent limitations in the design of such hybrids. Achieving an
efficacious concentration of the antibacterial at each target site is more problematic, although it can be achieved as evidenced by the re-purposed drug auranofin (see
Chap. 1, Fig. 1.4 for the structure), which shows promising multi-site activity against
Gram-positive pathogens (Thangamani et al. 2016), and against Mycobacterium
tuberculosis in vitro (Harbut et al. 2015). Auranofin displays a complex interplay
of activities involving targets in the cell wall, DNA and bacterial protein synthesis,
but outer membrane permeability issues, together possibly with efflux pump activity
(e.g., AcrAB activity), compromised Gram-negative efficacy and further structural
adjustments may be necessary to increase penetration; alternatively, drawing on other
work, pentamidine may be worth adding as a membrane disruptor (Stokes et al.
107
extract needs to done, tetrahydroamentoflavone is one of the significant components
in the active extract, and it is thus conceivable that incorporating elements of this
flavonoid structure in the hypothetical structure (Fig. 3.33a) might also show quorum
quenching activity. With such a compound there could thus be a DNA focus for two of
the interactions (A/B portion) while C might interfere with the NorA pump-mediated
efflux of the molecule in Staphylococcus aureus. Indicative assessment of the NorA
pump inhibitory activity would have merit in this process in order to highlight the
most likely designs to be of interest. Such assessments might usefully involve in silico
docking studies on a homology model of the pump for which an X-ray structure is
not currently available (Gupta et al. 2018; Zimmermann et al. 2019).
On a general note, other groupings of target recognition elements can be envisaged
which are not covered by types i–vi but which would extend the possible design
possibilities for future studies. By way of illustration, one could for example consider
structural types involving just two recognition elements, A and B, but with one having
two different binding sites and the second a different site for the triple activity. The
units A and B might then be linked by one or more extra linking atoms (A---B) or be
directly linked or fused or be linked by a common atom (AB). Further progression
of the fusion would then lead to condensed systems represented by A/B.
3.4 More Than Triple Action Hybrid Agents
One would be justified in asking whether incorporation of more than three separate
recognition sites in the one hybrid molecule was a pipedream or was it a likely
possibility for multi-modal single molecule antibacterials? This author considers
that it is likely to be the latter on the basis of such intentionally designed agents
with potentially more than three separate activities in other areas being described, for
example, in the development of new antipsychotic drugs (Zajdel et al. 2018). Hybrids
were deliberately designed for interactions with greater than three receptor or receptor
sub-type sites and included structural elements known to favour selective interactions
with monoaminergic receptors; both agonistic and antagonistic interactions were
observed depending on the receptor, together with SERT blockade in a selected
instance.
But there are inherent limitations in the design of such hybrids. Achieving an
efficacious concentration of the antibacterial at each target site is more problematic, although it can be achieved as evidenced by the re-purposed drug auranofin (see
Chap. 1, Fig. 1.4 for the structure), which shows promising multi-site activity against
Gram-positive pathogens (Thangamani et al. 2016), and against Mycobacterium
tuberculosis in vitro (Harbut et al. 2015). Auranofin displays a complex interplay
of activities involving targets in the cell wall, DNA and bacterial protein synthesis,
but outer membrane permeability issues, together possibly with efflux pump activity
(e.g., AcrAB activity), compromised Gram-negative efficacy and further structural
adjustments may be necessary to increase penetration; alternatively, drawing on other
work, pentamidine may be worth adding as a membrane disruptor (Stokes et al.