178
5 Future Possibilities
is an essential nutrient for many bacteria and access to it could be cut off resulting
in a cessation of replication and ultimately cell death for the bacterium within the
host cell. Host cell biochemistry is altered which then has a negative impact on
intracellular bacteria (Cockburn et al. 2019). Resistance is considered to be unlikely
to develop as the compounds target a host pathway which the bacteria require for
survival. This result though has broader implications for multi-action antibacterial
design, although it would be better to try and move away from antidepressant structural motifs in any composite multi-targeting design in view of potential issues which
may arise in giving antidepressants to non-depressed healthy people.
5.5 DNA and RNA Level Modulation
Modulation of the DNA-RNA sphere in bacteria continues to be an important area
from the perspective of new antibacterials including multi-targeting approaches. This
momentum is likely to continue in the future and only some examples are indicated
in this section.
One key area involves inhibition of DNA replication. Inhibition or suppression of
DNA replication via interference with the sliding clamp (β-clamp) as the target for the
antibacterial activity of some non-steroidal anti-inflammatory drugs as well as other
compound types has great promise for the development of new antibacterials (Yin
et al. 2014; Altieri and Kelman 2018). Additionally, detailed molecular understanding
of the intricate bacterial DNA replication processes from cutting edge observational
techniques, particularly single molecule techniques (Robinson and van Oijen 2013),
will continue to aid the design process for specific inhibitors.
A further target for antibacterials involves counteracting bacterial DNA repair
through small molecule interference with DNA repair proteins that act on Holliday
junctions which are vital intermediates in many repair pathways. From a compound
library screen, Rideout et al. (2011) discovered a number of interesting disubstituted pyrrolidine derivatives incorporating 5-membered ring cyclic guanidine units
in each of the substituents. These compounds were shown to interfere with the
resolution of Holliday junctions in vitro and were also potent growth inhibitors of
both Gram-negative and Gram-positive bacteria, particularly the latter. Earlier work
by Gunderson and Segall had identified Holliday junction-trapping hexapeptides
(Gunderson and Segall 2006) but these are quite large molecules.
Transcriptional regulators have also been identified as important targets for
different antibacterial approaches (González et al. 2018). Another potential avenue
of attack is to consider epigenetic drug targets in bacteria arguing by inference from
the insightful work of Baell and colleagues (Baell et al. 2018) who described small
molecule inhibitors of particular histone acetyltransferases that induce senescence
and arrest the growth of tumours; in effect the cells go to ‘sleep’. Their most active
compound was the aroylsulfonohydrazide WM-8014 (Fig. 5.15). Different targets
with a similar function seem possible in bacteria (Hu et al. 2010a).
5 Future Possibilities
is an essential nutrient for many bacteria and access to it could be cut off resulting
in a cessation of replication and ultimately cell death for the bacterium within the
host cell. Host cell biochemistry is altered which then has a negative impact on
intracellular bacteria (Cockburn et al. 2019). Resistance is considered to be unlikely
to develop as the compounds target a host pathway which the bacteria require for
survival. This result though has broader implications for multi-action antibacterial
design, although it would be better to try and move away from antidepressant structural motifs in any composite multi-targeting design in view of potential issues which
may arise in giving antidepressants to non-depressed healthy people.
5.5 DNA and RNA Level Modulation
Modulation of the DNA-RNA sphere in bacteria continues to be an important area
from the perspective of new antibacterials including multi-targeting approaches. This
momentum is likely to continue in the future and only some examples are indicated
in this section.
One key area involves inhibition of DNA replication. Inhibition or suppression of
DNA replication via interference with the sliding clamp (β-clamp) as the target for the
antibacterial activity of some non-steroidal anti-inflammatory drugs as well as other
compound types has great promise for the development of new antibacterials (Yin
et al. 2014; Altieri and Kelman 2018). Additionally, detailed molecular understanding
of the intricate bacterial DNA replication processes from cutting edge observational
techniques, particularly single molecule techniques (Robinson and van Oijen 2013),
will continue to aid the design process for specific inhibitors.
A further target for antibacterials involves counteracting bacterial DNA repair
through small molecule interference with DNA repair proteins that act on Holliday
junctions which are vital intermediates in many repair pathways. From a compound
library screen, Rideout et al. (2011) discovered a number of interesting disubstituted pyrrolidine derivatives incorporating 5-membered ring cyclic guanidine units
in each of the substituents. These compounds were shown to interfere with the
resolution of Holliday junctions in vitro and were also potent growth inhibitors of
both Gram-negative and Gram-positive bacteria, particularly the latter. Earlier work
by Gunderson and Segall had identified Holliday junction-trapping hexapeptides
(Gunderson and Segall 2006) but these are quite large molecules.
Transcriptional regulators have also been identified as important targets for
different antibacterial approaches (González et al. 2018). Another potential avenue
of attack is to consider epigenetic drug targets in bacteria arguing by inference from
the insightful work of Baell and colleagues (Baell et al. 2018) who described small
molecule inhibitors of particular histone acetyltransferases that induce senescence
and arrest the growth of tumours; in effect the cells go to ‘sleep’. Their most active
compound was the aroylsulfonohydrazide WM-8014 (Fig. 5.15). Different targets
with a similar function seem possible in bacteria (Hu et al. 2010a).