5.2 New Combinations and Single Molecules with Multi-activity …
163
2018) also suggests it might be feasible to develop hybrids targeting both MsbA and
LpxA and/or LpxD. Also exploring commonalities in design for lipid A biosynthesis
enzyme inhibitors and then lipid A transporters would be a good approach in view
of substrate similarities.
5.3 Search for Different Chemical Structure Types
Identifying and accessing unprecedented molecular scaffolds for incorporation in
new hybrid and prodrug designs is still very relevant. Exploration at the same time of
novel and unusual functional groups, such as the pentafluorosulfanyl group (referred
to in Chap. 3, Sect. 3.3.4.1) can further extend the boundaries of new structural
space. The new scaffolds could come from many sources and it will be increasingly
important to be innovative in the search thinking well outside the norm and proposing
unusual skeletal atoms and possible new functional groups incorporating elements
from many parts of the Periodic Table. New directions in diversity-oriented synthesis
are also likely to reveal a plethora of small molecules with increasingly complex
molecular structural arrays and new bioactivities (Gerry and Schreiber 2020).
As a number of antibacterial natural products have shown at least dual modes of
activity it would not be unreasonable to look further for new natural sources based on
identifying silent operons in bacteria and other competitive microorganisms which
if activated might express new multiply active compounds (Cully 2018; Ahmad
et al. 2020). There is still a vast scope for research in this area and only some
suggestions are touched on here. Exemplary strategies to establish viable platforms
for antibacterial discovery, including previously non-accessible natural origins, have
been thoroughly described (Lewis 2013; Brüssow 2017; Lok 2015). Again there is
a need though to think well outside the square here and broaden the potential for
serendipitous discoveries, including further ‘mining the microbial dark matter’ for
new antibiotics (Lok 2015).
In the environment, many organisms, including microorganism, produce antibiotics as a self-protection mechanism to control or ward off attack by bacteria. Identifying such producers and the nature of the compounds and how they might act is
an ongoing and exciting field of endeavour. Biorational approaches are particularly
powerful for such discovery with one example being, among a number of others,
the identification of the natural product tyriverdin, as a potent bacteriostatic agent
isolated from the egg masses of the marine mollusc Dicathais orbita (Benkendorff
2013; Benkendorff et al. 2000).
It may also be beneficial to look again at seemingly disparate areas at the microbiological level in biorational searches. For example, looking for bacteria-protozoa
defensive interactions. There are a number of reports of protozoa producing antibacterials including the perylenequinonoid (hypericin-related) derivative blepharismin
from the ciliated protozoan Blepharisma japonicum (Pant et al. 1997). Blepharismin
displayed good activity against MRSA but this activity was higher with photoactivation suggesting the possible involvement of singlet oxygen-derived reactive species in
163
2018) also suggests it might be feasible to develop hybrids targeting both MsbA and
LpxA and/or LpxD. Also exploring commonalities in design for lipid A biosynthesis
enzyme inhibitors and then lipid A transporters would be a good approach in view
of substrate similarities.
5.3 Search for Different Chemical Structure Types
Identifying and accessing unprecedented molecular scaffolds for incorporation in
new hybrid and prodrug designs is still very relevant. Exploration at the same time of
novel and unusual functional groups, such as the pentafluorosulfanyl group (referred
to in Chap. 3, Sect. 3.3.4.1) can further extend the boundaries of new structural
space. The new scaffolds could come from many sources and it will be increasingly
important to be innovative in the search thinking well outside the norm and proposing
unusual skeletal atoms and possible new functional groups incorporating elements
from many parts of the Periodic Table. New directions in diversity-oriented synthesis
are also likely to reveal a plethora of small molecules with increasingly complex
molecular structural arrays and new bioactivities (Gerry and Schreiber 2020).
As a number of antibacterial natural products have shown at least dual modes of
activity it would not be unreasonable to look further for new natural sources based on
identifying silent operons in bacteria and other competitive microorganisms which
if activated might express new multiply active compounds (Cully 2018; Ahmad
et al. 2020). There is still a vast scope for research in this area and only some
suggestions are touched on here. Exemplary strategies to establish viable platforms
for antibacterial discovery, including previously non-accessible natural origins, have
been thoroughly described (Lewis 2013; Brüssow 2017; Lok 2015). Again there is
a need though to think well outside the square here and broaden the potential for
serendipitous discoveries, including further ‘mining the microbial dark matter’ for
new antibiotics (Lok 2015).
In the environment, many organisms, including microorganism, produce antibiotics as a self-protection mechanism to control or ward off attack by bacteria. Identifying such producers and the nature of the compounds and how they might act is
an ongoing and exciting field of endeavour. Biorational approaches are particularly
powerful for such discovery with one example being, among a number of others,
the identification of the natural product tyriverdin, as a potent bacteriostatic agent
isolated from the egg masses of the marine mollusc Dicathais orbita (Benkendorff
2013; Benkendorff et al. 2000).
It may also be beneficial to look again at seemingly disparate areas at the microbiological level in biorational searches. For example, looking for bacteria-protozoa
defensive interactions. There are a number of reports of protozoa producing antibacterials including the perylenequinonoid (hypericin-related) derivative blepharismin
from the ciliated protozoan Blepharisma japonicum (Pant et al. 1997). Blepharismin
displayed good activity against MRSA but this activity was higher with photoactivation suggesting the possible involvement of singlet oxygen-derived reactive species in