26
2 Antibacterial Combinations
have shown promise in partially inhibiting AgrA- mediated expression of virulence
factors and the quorum sensing system in Staphylococcus aureus (Bezar et al. 2019).
In a quite different approach, bacterial growth may be promoted above normal by
the second component in the combination in order to make bacteria more sensitive to
the other antibacterial component. The concept has been pursued recently by using a
sugar (to promote growth) and a terminal electron acceptor to increase the potency of
some quinolone antibiotics (Gutierrez et al. 2017). This suggests that the somewhat
counter-intuitive idea of promoting growth to increase sensitivity to antibacterials
has potential to be more widely applied.
2.1.1.2 A (Antibacterial) and B (Antibacterial)
With this combination type each component would be directly antibacterial through
a single interaction with a bacterial target in each case.
A range of different antibacterials in such dual combinations have been studied or
are under investigation (Tyers and Wright 2019; Domalaon et al. 2018) and only one
illustrative selected recent report is discussed here. For example, one line of investigation has been to try and develop trimethoprim analogues to overcome dihydrofolate
reductase (DHFR) resistance which compromises the activity of this antibacterial.
Trimethoprim has been used extensively clinically in combination with sulfonamides
which inhibit dihydropteroate synthetase (DHPS) in the folate pathway. A number
of trimethoprim analogues incorporating one or two imidazo-ring fusions to the key
pyrimidine core of trimethoprim were prepared. These derivatives incorporated one
or both amino substituent group nitrogens of the diaminopyrimidine unit in trimethoprim, and one derivative, a mono imidazo ring-fused analogue, showed promising
synergistic in vitro potency in combination with the dihydropteroate synthetase
inhibitor sulfamethoxazole in Staphylococcus aureus and Escherichia coli, although
not quite as good as trimethoprim itself. These derivatives could be promising DHFR
inhibitor lead compounds (Pedrola et al. 2019). Limitations are apparent though and
these new compounds were not active against Pseudomonas aeruginosa either alone
or in combination with sulfamethoxazole, possibly due to permeability and/or efflux
issues.
2.1.2 Dual Combinations Resulting in Three or More Actions
With these dual combinations and three or more target interactions, the classification
of combination sub-types becomes quite complex. However, for simplicity one can
designate four sub-types using the A, B, C, D notation for each molecular component
or part of each component for basic classification purposes as follows:
2 Antibacterial Combinations
have shown promise in partially inhibiting AgrA- mediated expression of virulence
factors and the quorum sensing system in Staphylococcus aureus (Bezar et al. 2019).
In a quite different approach, bacterial growth may be promoted above normal by
the second component in the combination in order to make bacteria more sensitive to
the other antibacterial component. The concept has been pursued recently by using a
sugar (to promote growth) and a terminal electron acceptor to increase the potency of
some quinolone antibiotics (Gutierrez et al. 2017). This suggests that the somewhat
counter-intuitive idea of promoting growth to increase sensitivity to antibacterials
has potential to be more widely applied.
2.1.1.2 A (Antibacterial) and B (Antibacterial)
With this combination type each component would be directly antibacterial through
a single interaction with a bacterial target in each case.
A range of different antibacterials in such dual combinations have been studied or
are under investigation (Tyers and Wright 2019; Domalaon et al. 2018) and only one
illustrative selected recent report is discussed here. For example, one line of investigation has been to try and develop trimethoprim analogues to overcome dihydrofolate
reductase (DHFR) resistance which compromises the activity of this antibacterial.
Trimethoprim has been used extensively clinically in combination with sulfonamides
which inhibit dihydropteroate synthetase (DHPS) in the folate pathway. A number
of trimethoprim analogues incorporating one or two imidazo-ring fusions to the key
pyrimidine core of trimethoprim were prepared. These derivatives incorporated one
or both amino substituent group nitrogens of the diaminopyrimidine unit in trimethoprim, and one derivative, a mono imidazo ring-fused analogue, showed promising
synergistic in vitro potency in combination with the dihydropteroate synthetase
inhibitor sulfamethoxazole in Staphylococcus aureus and Escherichia coli, although
not quite as good as trimethoprim itself. These derivatives could be promising DHFR
inhibitor lead compounds (Pedrola et al. 2019). Limitations are apparent though and
these new compounds were not active against Pseudomonas aeruginosa either alone
or in combination with sulfamethoxazole, possibly due to permeability and/or efflux
issues.
2.1.2 Dual Combinations Resulting in Three or More Actions
With these dual combinations and three or more target interactions, the classification
of combination sub-types becomes quite complex. However, for simplicity one can
designate four sub-types using the A, B, C, D notation for each molecular component
or part of each component for basic classification purposes as follows: