5.4 New Modes of Action/New Targets
175
muramycin nucleoside-based antibiotics as a foundation for new optimized analogue
development. There would seem to considerable potential here for hybrid or prodrug
design to include cephalosporin or similar units. The development of such hybrids or
prodrugs could usefully be based on the sites identified for MraY inhibition by Mashalidis et al. (2019) as ‘druggable hotspots’ on the enzyme. Some six such hotspots have
been identified as a result of extensive co-crystallization studies with known types
of inhibitors and subsequent X-ray crystallographic analysis, apart from the essential common uridine binding site. Perhaps a fluoroquinolone could also be modified
to bind to one such hotspot while still retaining the gyrase and topoisomerase IV
inhibitory activity.
As introduced in Chap. 1 (Sect. 1.3.4), the bacterial survival strategy of
programmed cell death in bacterial communities (Peeters and de Jonge 2018) may
also be a potential bacterial vulnerability in which unprogrammed, or premature,
cell death might be initiated via small molecule interventions and enzyme interactions, which could be detrimental to the bacterial community public good (Tanouchi
et al. 2013). Careful structural design work would be required for such molecules
with appropriate enzyme multi-targeting. A potential issue may be that perhaps there
are endogenous molecules in bacteria which sense premature bacterial cell death and
which then initiate other actions to locate and nullify the problem. If such compounds
were identified in the future then interference with the actions of any such molecules
could be a fruitful new avenue for antibacterial research.
Other protein targets
Bacterial chaperone system
Bacterial chaperones afford other opportunities for antibacterial interventions and
the use of triply active compounds to effectively target these chaperones such as
HSP70, known as DnaK, and it’s two partner proteins (Alix 2013). Targeting bacterial
chaperones in the bacterial proteostasis system for the treatment of tuberculosis has
been reported by Lupoli et al. (2018) and the prospects for more such selective
targeting developments are likely to be good.
The chaperonins GroEL and BroES are critical for bacterial growth and small
molecule inhibitors are also being actively pursued. These inhibitors have been
identified from large library screening (Abdeen et al. 2016, 2018; Stevens et al.
2019).
An interesting development related to the bacterial chaperone context is the
discovery, from a screen of Photorhabdus symbionts of nematode microbiomes (see
also Sect. 5.3 for other approaches), of the antibiotic darobactin, which is selectively
toxic to Gram-negative pathogens in vitro and in mouse models of infection (Imai
et al. 2019; and useful explanatory comment on the work by York 2020). Darobactin
(Fig. 5.12) is a modified hexapeptide with two unusual embedded macrocyclic
components and it acts through interference with BamA a chaperone and translocator
which folds outer membrane proteins. While darobactin-resistant mutant strains of
Escherichia coli could be induced in laboratory culture, this result reinforces the
175
muramycin nucleoside-based antibiotics as a foundation for new optimized analogue
development. There would seem to considerable potential here for hybrid or prodrug
design to include cephalosporin or similar units. The development of such hybrids or
prodrugs could usefully be based on the sites identified for MraY inhibition by Mashalidis et al. (2019) as ‘druggable hotspots’ on the enzyme. Some six such hotspots have
been identified as a result of extensive co-crystallization studies with known types
of inhibitors and subsequent X-ray crystallographic analysis, apart from the essential common uridine binding site. Perhaps a fluoroquinolone could also be modified
to bind to one such hotspot while still retaining the gyrase and topoisomerase IV
inhibitory activity.
As introduced in Chap. 1 (Sect. 1.3.4), the bacterial survival strategy of
programmed cell death in bacterial communities (Peeters and de Jonge 2018) may
also be a potential bacterial vulnerability in which unprogrammed, or premature,
cell death might be initiated via small molecule interventions and enzyme interactions, which could be detrimental to the bacterial community public good (Tanouchi
et al. 2013). Careful structural design work would be required for such molecules
with appropriate enzyme multi-targeting. A potential issue may be that perhaps there
are endogenous molecules in bacteria which sense premature bacterial cell death and
which then initiate other actions to locate and nullify the problem. If such compounds
were identified in the future then interference with the actions of any such molecules
could be a fruitful new avenue for antibacterial research.
Other protein targets
Bacterial chaperone system
Bacterial chaperones afford other opportunities for antibacterial interventions and
the use of triply active compounds to effectively target these chaperones such as
HSP70, known as DnaK, and it’s two partner proteins (Alix 2013). Targeting bacterial
chaperones in the bacterial proteostasis system for the treatment of tuberculosis has
been reported by Lupoli et al. (2018) and the prospects for more such selective
targeting developments are likely to be good.
The chaperonins GroEL and BroES are critical for bacterial growth and small
molecule inhibitors are also being actively pursued. These inhibitors have been
identified from large library screening (Abdeen et al. 2016, 2018; Stevens et al.
2019).
An interesting development related to the bacterial chaperone context is the
discovery, from a screen of Photorhabdus symbionts of nematode microbiomes (see
also Sect. 5.3 for other approaches), of the antibiotic darobactin, which is selectively
toxic to Gram-negative pathogens in vitro and in mouse models of infection (Imai
et al. 2019; and useful explanatory comment on the work by York 2020). Darobactin
(Fig. 5.12) is a modified hexapeptide with two unusual embedded macrocyclic
components and it acts through interference with BamA a chaperone and translocator
which folds outer membrane proteins. While darobactin-resistant mutant strains of
Escherichia coli could be induced in laboratory culture, this result reinforces the