172
5 Future Possibilities
PqsR or of PqsD and PqsR, are discussed. Further studies on possibly triple
targeting inhibitors would be of great interest.
(ii) increasing the application of mobile ‘mini’ receptors to strongly complex
the extra-cellular sensor. Such ‘Pied piper’ or ‘sponge’ therapeutics could
be designed to lure and strongly bind quorum sensing molecules including
by encapsulation through multiple non-bonded interactions with one or more
ligand molecules resulting in a Russian-doll type complex.
(iii) inhibition of sensor-receptor binding through a competitive or noncompetitive antagonist. Small molecule autoinducer analogues capable of
modulating the SdiA quorum sensing receptor in Salmonella enterica serovar
Typhimurium via agonism or antagonism have been reported by Styles and
Blackwell (2018). Nizalapur et al. (2016) have also reported on a number
of structurally novel inhibitors of bacterial quorum sensing based on Narylisatin-based-glyoxamide derivatives which are accessible synthetically
via the reaction of N-aryl isatins with cyclic and acyclic amines resulting
in isatin ring opening from attack at the C2 lactam carbonyl group. One
of these derivatives, an ethyl glycinate-substituted glyoxamide, exhibited an
interesting activity profile with moderate quorum sensing inhibitory activity
against a LuxR-expressing Escherichia coli strain and also against a strain of
Pseudomonas aeruginosa expressing LasR receptor. Computer-based docking
studies with LasR protein indicated the important role of hydrogen bonding
interactions in the docking of this compound with the highest quorum sensing
inhibitory (QSI) activity.
Biswas et al. (2018) also studied some fimbrolide analogues as quorum sensing
inhibitors in a Pseudomonas aeruginosa-based assay, and interestingly one of the
compounds exhibited quorum sensing inhibitory activity as well as bactericidal
activity suggesting at least dual activity. This offers further potential for extension
to triply active hybrids.
It should be noted here, though, that although the approach of targeting the QS
system is thought to be one which will not lead to a bacterial resistance response,
this is not necessarily the case as demonstrated by Maeda et al. (2012). This work is
referenced in the useful review by Arvanitis et al. (2013) which includes coverage
on using Pseudomonas aeruginosa in Caenorhabditis elegans as the in vivo model
for assessing the effects of exposure to an agent that targets quorum sensing.
Selective modulation of bacterial kinases
Bacterial kinases are another bacterial signalling system which can be targeted.
Some inhibitors of penicillin-binding-protein and serine/threonine kinase-associated
(PASTA) kinases are relevant as these kinases have a role in mediating resistance
to β–lactam antibiotics. These dual enzyme inhibitors, for example GSK690693
(Fig. 5.8), are imidazopyridine aminofurazans (Schaenzer et al. 2017). GSK690693
has been shown to sensitize the bacterial pathogen Listeria monocytogenes to the
β-lactam antibiotic ceftriaxone. Extensions here to involve multi-targeting suggest a
5 Future Possibilities
PqsR or of PqsD and PqsR, are discussed. Further studies on possibly triple
targeting inhibitors would be of great interest.
(ii) increasing the application of mobile ‘mini’ receptors to strongly complex
the extra-cellular sensor. Such ‘Pied piper’ or ‘sponge’ therapeutics could
be designed to lure and strongly bind quorum sensing molecules including
by encapsulation through multiple non-bonded interactions with one or more
ligand molecules resulting in a Russian-doll type complex.
(iii) inhibition of sensor-receptor binding through a competitive or noncompetitive antagonist. Small molecule autoinducer analogues capable of
modulating the SdiA quorum sensing receptor in Salmonella enterica serovar
Typhimurium via agonism or antagonism have been reported by Styles and
Blackwell (2018). Nizalapur et al. (2016) have also reported on a number
of structurally novel inhibitors of bacterial quorum sensing based on Narylisatin-based-glyoxamide derivatives which are accessible synthetically
via the reaction of N-aryl isatins with cyclic and acyclic amines resulting
in isatin ring opening from attack at the C2 lactam carbonyl group. One
of these derivatives, an ethyl glycinate-substituted glyoxamide, exhibited an
interesting activity profile with moderate quorum sensing inhibitory activity
against a LuxR-expressing Escherichia coli strain and also against a strain of
Pseudomonas aeruginosa expressing LasR receptor. Computer-based docking
studies with LasR protein indicated the important role of hydrogen bonding
interactions in the docking of this compound with the highest quorum sensing
inhibitory (QSI) activity.
Biswas et al. (2018) also studied some fimbrolide analogues as quorum sensing
inhibitors in a Pseudomonas aeruginosa-based assay, and interestingly one of the
compounds exhibited quorum sensing inhibitory activity as well as bactericidal
activity suggesting at least dual activity. This offers further potential for extension
to triply active hybrids.
It should be noted here, though, that although the approach of targeting the QS
system is thought to be one which will not lead to a bacterial resistance response,
this is not necessarily the case as demonstrated by Maeda et al. (2012). This work is
referenced in the useful review by Arvanitis et al. (2013) which includes coverage
on using Pseudomonas aeruginosa in Caenorhabditis elegans as the in vivo model
for assessing the effects of exposure to an agent that targets quorum sensing.
Selective modulation of bacterial kinases
Bacterial kinases are another bacterial signalling system which can be targeted.
Some inhibitors of penicillin-binding-protein and serine/threonine kinase-associated
(PASTA) kinases are relevant as these kinases have a role in mediating resistance
to β–lactam antibiotics. These dual enzyme inhibitors, for example GSK690693
(Fig. 5.8), are imidazopyridine aminofurazans (Schaenzer et al. 2017). GSK690693
has been shown to sensitize the bacterial pathogen Listeria monocytogenes to the
β-lactam antibiotic ceftriaxone. Extensions here to involve multi-targeting suggest a