2.1 Introduction
23
2.1.1 Dual Combinations Resulting in Two Actions
The area of dual combinations for antibacterial therapy has been, and continues to
be, explored extensively and has been reviewed in detail most recently by Domalaon
et al. (2018) which includes, amongst other topics, a treatment of dual combinations
resulting in two actions. Another excellent recent review in this combination space is
that by Tyers and Wright (2019) which also has a good treatment of recent hybrids and
the theory associated with synergy plus associated terms. They classify synergistic
antibiotic combinations (dual) in three categories: congruous, syncretic and coalistic.
With a congruous pair the components target two distinct essential targets, while the
syncretic case covers one component targeting an essential bacterial process and the
other non-directly antibacterial component interacting with what is designated as a
non-essential target or resistance element. In the last category neither component
would be antibacterial but could interact with target proteins which correspond to
synthetic lethal genetic interaction pairs resulting in specific chemical lethality. Such
combinations could result in very narrow-spectrum effects and further developments
in this area are likely to emerge in the future. For this section of the book, discussion is
concentrated on pairwise combinations in the first two categories. Significantly Tyres
and Wright also argue for multi-targeting approaches in new antibacterial designs.
The simplest combination matrix involves the combined administration of two
separate drugs. From an in vivo perspective, oral administration could involve two
separate tablets or a fixed dose combination in a single tablet (Prati et al. 2014).
This combination can be reduced to an A + B notation for drug A and drug B. With
this dual combination the two-sub-group classifications would then include in the
first sub-group (Sect. 2.1.1.1) the situation where one of the drugs (A) has a direct
antibacterial action through a single interaction with a single bacterial target, while
the second drug (B) would have a separate potentiating single interaction with another
target but not being directly antibacterial. In the second sub-group (Sect. 2.1.1.2) both
component (A) and component (B) might be directly antibacterial through a single
action each at two different targets or at different points on the same target.
While each drug in dual combinations often has one interaction site each, possibilities exist to extend the drug interaction site to more than one for either one or both
components resulting in a triple or higher order interaction spectrum as discussed in
the subsequent sub-sections of 2.1.2.
2.1.1.1 A (Antibacterial) and B (Non-direct Antibacterial)
In this sub-group, one component would be directly antibacterial and the other not but
potentiating or enhancing the activity of the other component. The latter compound
may act within or on the bacterium or outside it, as with quorum sensing antagonists
or inhibitors or other anti-virulence activities. The rationale in this particular scenario
is that by inhibiting quorum sensing, bacterial pathogenicity will be compromised
23
2.1.1 Dual Combinations Resulting in Two Actions
The area of dual combinations for antibacterial therapy has been, and continues to
be, explored extensively and has been reviewed in detail most recently by Domalaon
et al. (2018) which includes, amongst other topics, a treatment of dual combinations
resulting in two actions. Another excellent recent review in this combination space is
that by Tyers and Wright (2019) which also has a good treatment of recent hybrids and
the theory associated with synergy plus associated terms. They classify synergistic
antibiotic combinations (dual) in three categories: congruous, syncretic and coalistic.
With a congruous pair the components target two distinct essential targets, while the
syncretic case covers one component targeting an essential bacterial process and the
other non-directly antibacterial component interacting with what is designated as a
non-essential target or resistance element. In the last category neither component
would be antibacterial but could interact with target proteins which correspond to
synthetic lethal genetic interaction pairs resulting in specific chemical lethality. Such
combinations could result in very narrow-spectrum effects and further developments
in this area are likely to emerge in the future. For this section of the book, discussion is
concentrated on pairwise combinations in the first two categories. Significantly Tyres
and Wright also argue for multi-targeting approaches in new antibacterial designs.
The simplest combination matrix involves the combined administration of two
separate drugs. From an in vivo perspective, oral administration could involve two
separate tablets or a fixed dose combination in a single tablet (Prati et al. 2014).
This combination can be reduced to an A + B notation for drug A and drug B. With
this dual combination the two-sub-group classifications would then include in the
first sub-group (Sect. 2.1.1.1) the situation where one of the drugs (A) has a direct
antibacterial action through a single interaction with a single bacterial target, while
the second drug (B) would have a separate potentiating single interaction with another
target but not being directly antibacterial. In the second sub-group (Sect. 2.1.1.2) both
component (A) and component (B) might be directly antibacterial through a single
action each at two different targets or at different points on the same target.
While each drug in dual combinations often has one interaction site each, possibilities exist to extend the drug interaction site to more than one for either one or both
components resulting in a triple or higher order interaction spectrum as discussed in
the subsequent sub-sections of 2.1.2.
2.1.1.1 A (Antibacterial) and B (Non-direct Antibacterial)
In this sub-group, one component would be directly antibacterial and the other not but
potentiating or enhancing the activity of the other component. The latter compound
may act within or on the bacterium or outside it, as with quorum sensing antagonists
or inhibitors or other anti-virulence activities. The rationale in this particular scenario
is that by inhibiting quorum sensing, bacterial pathogenicity will be compromised