3.3 Triple Action Antibacterial Hybrid Agents
85
could potentially impart a new mechanism of action by dual or multiple target
interactions. Of the compounds assessed in this work, a ciprofloxacin-sulfanilamide
hybrid (CGS-20) showed activity in vitro against Gram-negative bacterial strains,
and Gram-positives, with MICs better than ciprofloxacin alone and comparable with
the cephalosporin antibiotic, Cefixime. Dual or multiple targeting by the hybrid was
not shown however (Tahir et al. 2019).
Siderophores have also been incorporated into triple action hybrids with the
siderophore being a recognition element required for transport of the molecule into
the bacterial cell. Such hybrids are based on the ‘Trojan horse’ approach. Nature uses
this approach with the sideromycins (e.g., the albomycins), bacterial metabolites with
a siderophore linked to an antibiotic moiety to attack other bacteria (Al Shaer et al.
2020). The linkage of siderophores to monobactam antibacterials offer considerable promise and not surprisingly this has been investigated significantly. One can
envisage possibly a monobactam-siderophore compound with antibacterial and βlactamase inhibitory activity as well (Decuyper et al. 2018), plus monobactams like
aztreonam, which has excellent Gram-negative antibacterial activity through binding
particularly to Penicillin Binding Proteins (PBPs) PBP3 and PBP1a, together with
non-susceptibility to metallo–β-lactamases but not serine-β-lactamases, which can
be co-expressed (Dean et al. 2018; Decuyper et al. 2018). The monobactam antibacterial, LYS228, may be better for inclusion in such a hybrid rather than aztreonam
as it is stable to most serine-β-lactamases as well as metallo–β-lactamases (Dean
et al. 2018). In research by Brown et al. (2013), pyridone-conjugated monobactam
derivatives have been described with good antibacterial activity against clinically
relevant Gram-negative bacteria. With these hybrids the hydroxypyridone pharmacophoric unit probably mediated binding to the siderophore receptors PiuA and
PirA, while the monobactam unit would bind to a penicillin binding protein PBP3
(in Pseudomonas aeruginosa; Han et al. 2010).
In a potential extension of this approach, if the siderophore receptor also recognises and transports a pre-formed Ga(III) complex of the hydroxypyridone unit then
perhaps this offers a way of selectively transporting Ga(III) intracellularly. If realised,
one would have a mixed hybrid-prodrug approach in this case which would involve
non-enzymatic release of the Ga(III) from the complex with the ligand still having
PBP binding activity. While Fe (III) and Ga (III) are of similar size and ligand binding
characteristics it may be possible to incorporate other ligands in the hybrid design
to better complex Ga (III) while still being recognised by the transporter system as a
substrate. It has been shown that Ga(III) has antibacterial and antibiofilm properties
through actions affecting a number of biosynthetic pathways (Rzhepishevska et al.
2011). The potential of gallium complexes in therapeutic applications, including as
antibacterials, has been reviewed by Lessa et al. (2012). Gallium (III) complexation in salicylidene acylhydrazides also could provide access to new multi-action
antibacterials. The ligands themselves are of interest as anti-virulence agents which
inhibit the type III secretion system in Gram-negative bacteria probably through
multi-targeting in the cell (Hakobyan et al. 2014).
With a catechol-based siderophore attached to a cephalosporin, Cefiderocol (S649266) has also shown potent activity against aerobic Gram-negative bacteria
85
could potentially impart a new mechanism of action by dual or multiple target
interactions. Of the compounds assessed in this work, a ciprofloxacin-sulfanilamide
hybrid (CGS-20) showed activity in vitro against Gram-negative bacterial strains,
and Gram-positives, with MICs better than ciprofloxacin alone and comparable with
the cephalosporin antibiotic, Cefixime. Dual or multiple targeting by the hybrid was
not shown however (Tahir et al. 2019).
Siderophores have also been incorporated into triple action hybrids with the
siderophore being a recognition element required for transport of the molecule into
the bacterial cell. Such hybrids are based on the ‘Trojan horse’ approach. Nature uses
this approach with the sideromycins (e.g., the albomycins), bacterial metabolites with
a siderophore linked to an antibiotic moiety to attack other bacteria (Al Shaer et al.
2020). The linkage of siderophores to monobactam antibacterials offer considerable promise and not surprisingly this has been investigated significantly. One can
envisage possibly a monobactam-siderophore compound with antibacterial and βlactamase inhibitory activity as well (Decuyper et al. 2018), plus monobactams like
aztreonam, which has excellent Gram-negative antibacterial activity through binding
particularly to Penicillin Binding Proteins (PBPs) PBP3 and PBP1a, together with
non-susceptibility to metallo–β-lactamases but not serine-β-lactamases, which can
be co-expressed (Dean et al. 2018; Decuyper et al. 2018). The monobactam antibacterial, LYS228, may be better for inclusion in such a hybrid rather than aztreonam
as it is stable to most serine-β-lactamases as well as metallo–β-lactamases (Dean
et al. 2018). In research by Brown et al. (2013), pyridone-conjugated monobactam
derivatives have been described with good antibacterial activity against clinically
relevant Gram-negative bacteria. With these hybrids the hydroxypyridone pharmacophoric unit probably mediated binding to the siderophore receptors PiuA and
PirA, while the monobactam unit would bind to a penicillin binding protein PBP3
(in Pseudomonas aeruginosa; Han et al. 2010).
In a potential extension of this approach, if the siderophore receptor also recognises and transports a pre-formed Ga(III) complex of the hydroxypyridone unit then
perhaps this offers a way of selectively transporting Ga(III) intracellularly. If realised,
one would have a mixed hybrid-prodrug approach in this case which would involve
non-enzymatic release of the Ga(III) from the complex with the ligand still having
PBP binding activity. While Fe (III) and Ga (III) are of similar size and ligand binding
characteristics it may be possible to incorporate other ligands in the hybrid design
to better complex Ga (III) while still being recognised by the transporter system as a
substrate. It has been shown that Ga(III) has antibacterial and antibiofilm properties
through actions affecting a number of biosynthetic pathways (Rzhepishevska et al.
2011). The potential of gallium complexes in therapeutic applications, including as
antibacterials, has been reviewed by Lessa et al. (2012). Gallium (III) complexation in salicylidene acylhydrazides also could provide access to new multi-action
antibacterials. The ligands themselves are of interest as anti-virulence agents which
inhibit the type III secretion system in Gram-negative bacteria probably through
multi-targeting in the cell (Hakobyan et al. 2014).
With a catechol-based siderophore attached to a cephalosporin, Cefiderocol (S649266) has also shown potent activity against aerobic Gram-negative bacteria