1.5 Ways to Achieve Multi-action Effects
15
for example, is a discussion of berberine-derived hybrid multifunctional compounds
as potential drugs for the treatment of Alzheimer’s disease through multiple activities
including suppression of Aβ protein aggregation, antioxidant activity, and acetylcholinesterase and butyrylcholinesterase inhibition. A tacrine-based trihybrid multifunctional derivative has also been described which incorporates a terminal ONO 2
moiety as a nitric oxide (NO) donor; the NO released in vivo could then also have
further activities (Bansal and Silakari 2014). The general principles elaborated in the
design of these potential drugs for Alzheimer’s disease could potentially be utilised
in the design of triple or higher action drugs for the treatment of bacterial diseases.
To exemplify this more specifically for triple action agents, this could mean theoretically interacting with: (i) three separate sites (A
, B
, C
) on the one biomolecule
(e.g. a protein) or (ii) two different biomolecules, one with one interacting site
(A
) and the other with two different sites (B
, C
), or (iii) three different target
biomolecules each with a different single binding site (A
or B
or C
), plus permutations of the combination A
, B
, C
. A total of six permutations are possible in
type (i) assuming no asymmetric elements are involved. With just two sites (e.g.,
B
, C
) on the one biomolecule, then a total of four permutations are possible. The
resultant activities may be directly antibacterial or have indirect effects increasing
design possibilities. In the case of three possible targets one or two of them could
be indirect while still maintaining one direct antibacterial interaction or all three
could be indirect but ultimately result in bacterial death or stasis. These sites may be
intra-cellular, in the cell wall, or near-extracellular.
But, as mentioned, one can also consider combinations of drugs rather than hybrids
to achieve multi-targeting objectives. Combinations can involve the administration
of directly active antibacterials with or without indirectly acting compounds or adjuvants. The actions of different antibacterials or adjuvants may be synergistic (potentiating) (Bottegoni and Cavalli 2017), have no net increased or decreased effect (additive), or be antagonistic. Multi-action combinations are discussed in further detail
in Chap. 2 of this book and their significance in informing the design of potential
multi-action hybrids is considered in Chap. 3.
One of the proposed key advantages of multiple action single agents (administered
as is or as prodrugs) or combinations of single agents is that bacterial resistance is less
likely to develop. However it should be noted that development of resistance is still
feasible even though less likely. For example it has been shown that resistance to the
dual action antibiotic gepotidacin (a triazaacenaphthylene derivative; GlaxoSmith
Kline), which selectively inhibits both bacterial DNA gyrase and topoisomerase IV
enzymes involved in bacterial replication, can develop in Klebsiella pneumoniae via
stepping mutations i.e. a combination of two specific mutations (but not both at the
same time which would be difficult). Also the resistant mutant Klebsiella pneumoniae
was still as virulent as the wild type susceptible strain in a mouse model pathogenicity
test (Szili et al. 2019). Also in dual combination treatments resistance can develop
in one of the two components as seen with the dual ceftriaxone and azithromycin
treatment trial of gonorrhoea in Australia in 2014, which indicated susceptibility to
ceftriaxone was retained, but saw a worrying rise in the resistance to azithromycin
of Neisseria gonorrhoea (Autralian Commission on Safety and Quality in Health
15
for example, is a discussion of berberine-derived hybrid multifunctional compounds
as potential drugs for the treatment of Alzheimer’s disease through multiple activities
including suppression of Aβ protein aggregation, antioxidant activity, and acetylcholinesterase and butyrylcholinesterase inhibition. A tacrine-based trihybrid multifunctional derivative has also been described which incorporates a terminal ONO 2
moiety as a nitric oxide (NO) donor; the NO released in vivo could then also have
further activities (Bansal and Silakari 2014). The general principles elaborated in the
design of these potential drugs for Alzheimer’s disease could potentially be utilised
in the design of triple or higher action drugs for the treatment of bacterial diseases.
To exemplify this more specifically for triple action agents, this could mean theoretically interacting with: (i) three separate sites (A
, B
, C
) on the one biomolecule
(e.g. a protein) or (ii) two different biomolecules, one with one interacting site
(A
) and the other with two different sites (B
, C
), or (iii) three different target
biomolecules each with a different single binding site (A
or B
or C
), plus permutations of the combination A
, B
, C
. A total of six permutations are possible in
type (i) assuming no asymmetric elements are involved. With just two sites (e.g.,
B
, C
) on the one biomolecule, then a total of four permutations are possible. The
resultant activities may be directly antibacterial or have indirect effects increasing
design possibilities. In the case of three possible targets one or two of them could
be indirect while still maintaining one direct antibacterial interaction or all three
could be indirect but ultimately result in bacterial death or stasis. These sites may be
intra-cellular, in the cell wall, or near-extracellular.
But, as mentioned, one can also consider combinations of drugs rather than hybrids
to achieve multi-targeting objectives. Combinations can involve the administration
of directly active antibacterials with or without indirectly acting compounds or adjuvants. The actions of different antibacterials or adjuvants may be synergistic (potentiating) (Bottegoni and Cavalli 2017), have no net increased or decreased effect (additive), or be antagonistic. Multi-action combinations are discussed in further detail
in Chap. 2 of this book and their significance in informing the design of potential
multi-action hybrids is considered in Chap. 3.
One of the proposed key advantages of multiple action single agents (administered
as is or as prodrugs) or combinations of single agents is that bacterial resistance is less
likely to develop. However it should be noted that development of resistance is still
feasible even though less likely. For example it has been shown that resistance to the
dual action antibiotic gepotidacin (a triazaacenaphthylene derivative; GlaxoSmith
Kline), which selectively inhibits both bacterial DNA gyrase and topoisomerase IV
enzymes involved in bacterial replication, can develop in Klebsiella pneumoniae via
stepping mutations i.e. a combination of two specific mutations (but not both at the
same time which would be difficult). Also the resistant mutant Klebsiella pneumoniae
was still as virulent as the wild type susceptible strain in a mouse model pathogenicity
test (Szili et al. 2019). Also in dual combination treatments resistance can develop
in one of the two components as seen with the dual ceftriaxone and azithromycin
treatment trial of gonorrhoea in Australia in 2014, which indicated susceptibility to
ceftriaxone was retained, but saw a worrying rise in the resistance to azithromycin
of Neisseria gonorrhoea (Autralian Commission on Safety and Quality in Health