86
3 Single Molecule Non-cleavable Multiply Active Antibacterials
including multi-drug resistant Gram-negative pathogens (Ito et al. 2016; Aoki et al.
2018). The catechol moiety in this hybrid is an efficient iron chelator and the complex
is actively transported into cells of Pseudomonas aeruginosa mediated by iron transporters. Binding of the hybrid mainly to penicillin binding protein 3 (PBP 3) but
also to PBP 2 has been demonstrated (Ito et al. 2018). It can be speculated that a
gallium (III) complex of Cefiderocol might also be worth investigation for ultimately
delivering gallium (III) intracellularly with consequent negative flow-on effects for
bacterial iron-based metabolic processes and biofilm formation (Górska et al. 2014).
Design principles for potential siderophore containing antibiotics, together with
applications to mycobacteria, are discussed by Miller et al. (2009). In their article,
Miller et al. also point out the siderophore-drug linker can be used for targeting and
be cleavable so the molecule would then be a prodrug if inactive prior to cleavage.
If non-cleavable it would be a hybrid.
A further extension of the Trojan horse design manifold might be to exploit the
requirements for zinc (II) and manganese (II) by bacteria and develop zincophores
and manganophores coupled to a dual action moiety such as ciprofloxacin, as long
as this would result in synergistic actions. Manganese (II) uptake is mediated by two
main types of membrane transport pathways involving ABC permeases and/or natural
resistance associated macrophage protein (NRAMP) transporters (Eijkelkamp et al.
2015); Mn (II) can affect virulence of Streptococci (Eijkelkamp et al. 2015).
Another hybrid with triple activity is that derived from a neomycin structural
template with a butirosin-based amide derivatisation of one of the amino groups in
the cyclohexane unit and introduction of a double bond and deoxygenation of another
sugar unit as observed in the antibiotic sisomycin. This chimeric trihybrid of elements
from sisomycin (top right sugar unit) and butirosin (top left amidic side chain) around
the neomycin core (Fig. 3.18 ) showed good activity against the ESKAPE pathogenic
bacteria (Maianti and Hanessian 2016; Parkes and Yule 2016). The effectiveness of
such a trihybrid of three antibacterial units augers well for the progression to other
designs involving three antibacterials which could be based, for example, on the
results from the evaluation protocols elaborated by Yeh and co-workers (Beppler
et al. 2016) for combinations of three agents. Such combinations, and potentially
others, are useful as a starting point in defining activity groupings in triple action
agent design.
The trihybrid (Fig. 3.18) was potently antibacterial due to transport and accumulation in the bacterial cell, interaction with the ribosomal target possibly via a number
of interaction sites plus the subsequent bactericidal action, and also avoidance or
evasion of the major types of aminoglycoside modifying enzymes. The possibility
of such evasion was an integral part of the design process for the trihybrid. This last
outcome is not formally an ‘action’ but it highlights the need to include such considerations in the design of multiply active hybrids. In other words one can consider
an approach of deliberate design for ‘non-activity’ expressed through eluding resistance enzymes (or efflux pumps) by inclusion of specific structural features, which
can have a major impact in terms of antibacterial potency or spectrum of activity so
it needs to be considered in the design context. Thus in the hybrid design process it
is important to deliberately consider how to avoid certain targets and avoidance can
3 Single Molecule Non-cleavable Multiply Active Antibacterials
including multi-drug resistant Gram-negative pathogens (Ito et al. 2016; Aoki et al.
2018). The catechol moiety in this hybrid is an efficient iron chelator and the complex
is actively transported into cells of Pseudomonas aeruginosa mediated by iron transporters. Binding of the hybrid mainly to penicillin binding protein 3 (PBP 3) but
also to PBP 2 has been demonstrated (Ito et al. 2018). It can be speculated that a
gallium (III) complex of Cefiderocol might also be worth investigation for ultimately
delivering gallium (III) intracellularly with consequent negative flow-on effects for
bacterial iron-based metabolic processes and biofilm formation (Górska et al. 2014).
Design principles for potential siderophore containing antibiotics, together with
applications to mycobacteria, are discussed by Miller et al. (2009). In their article,
Miller et al. also point out the siderophore-drug linker can be used for targeting and
be cleavable so the molecule would then be a prodrug if inactive prior to cleavage.
If non-cleavable it would be a hybrid.
A further extension of the Trojan horse design manifold might be to exploit the
requirements for zinc (II) and manganese (II) by bacteria and develop zincophores
and manganophores coupled to a dual action moiety such as ciprofloxacin, as long
as this would result in synergistic actions. Manganese (II) uptake is mediated by two
main types of membrane transport pathways involving ABC permeases and/or natural
resistance associated macrophage protein (NRAMP) transporters (Eijkelkamp et al.
2015); Mn (II) can affect virulence of Streptococci (Eijkelkamp et al. 2015).
Another hybrid with triple activity is that derived from a neomycin structural
template with a butirosin-based amide derivatisation of one of the amino groups in
the cyclohexane unit and introduction of a double bond and deoxygenation of another
sugar unit as observed in the antibiotic sisomycin. This chimeric trihybrid of elements
from sisomycin (top right sugar unit) and butirosin (top left amidic side chain) around
the neomycin core (Fig. 3.18 ) showed good activity against the ESKAPE pathogenic
bacteria (Maianti and Hanessian 2016; Parkes and Yule 2016). The effectiveness of
such a trihybrid of three antibacterial units augers well for the progression to other
designs involving three antibacterials which could be based, for example, on the
results from the evaluation protocols elaborated by Yeh and co-workers (Beppler
et al. 2016) for combinations of three agents. Such combinations, and potentially
others, are useful as a starting point in defining activity groupings in triple action
agent design.
The trihybrid (Fig. 3.18) was potently antibacterial due to transport and accumulation in the bacterial cell, interaction with the ribosomal target possibly via a number
of interaction sites plus the subsequent bactericidal action, and also avoidance or
evasion of the major types of aminoglycoside modifying enzymes. The possibility
of such evasion was an integral part of the design process for the trihybrid. This last
outcome is not formally an ‘action’ but it highlights the need to include such considerations in the design of multiply active hybrids. In other words one can consider
an approach of deliberate design for ‘non-activity’ expressed through eluding resistance enzymes (or efflux pumps) by inclusion of specific structural features, which
can have a major impact in terms of antibacterial potency or spectrum of activity so
it needs to be considered in the design context. Thus in the hybrid design process it
is important to deliberately consider how to avoid certain targets and avoidance can