4.2 Introduction to Prodrugs for Triple or Higher Action …
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against strains of Acinetobacter baumannii which produce large quantities of the
lactamase ADC-1, as well as against Escherichia coli and Pseudomonas aeruginosa.
The siderophore-mediated active transport coupled with β-lactamase induced drug
release is a powerful combination for overcoming drug resistant bacteria. Replacement of the oxazolidinone with ester-linked ciprofloxacin, a strategy also used by
Evans et al. (2019), while retaining the attached siderophore moiety, is suggested to
be of interest as long as the ester linkage remains intact prior to active uptake of the
conjugate.
Targeted antibacterial delivery in an inactive enterobactin-ciprofloxacin conjugate
prodrug (Fig. 4.2) was achieved through the enterobactin siderophore uptake mechanism in an Escherichia coli pathogenic strain which expressed the iroA gene cluster.
After uptake, hydrolysis of the siderophore enterobactin moiety by a particular cytoplasmic hydrolase IroD in this strain then results in intracellular release of the active
antibacterial (Neumann et al. 2018). Such bacterial enzyme specificity could be used
as the basis for the development of narrow spectrum antibacterials.
Some antibiotics may also produce reactive oxygen species (ROSs) which could
complement other activity pathways, although this ROS proposal has been criticized
by others (Owens 2013). Interestingly hydrogen peroxide released by Streptococcus
pneumoniae inhibits inflammasomes resulting in immune suppression (Erttmann and
Gekara 2019). The bacteria avoid attack by the immune system, but how Streptococcus pneumoniae maintains high resistance itself to hydrogen peroxide is still
incompletely understood.
Reactive oxygen species could be useful, however, in triggering the release of
antibacterials in situ. In the anti-cancer context, Noh and co-workers reported on
the use of a hydrid drug responsive to dual stimuli which increased the death of
cancer cells via enhancement of oxidative stress (Noh et al. 2015). The hybrid
was based on a substituted carbonate diester moiety, with one substituent group
being the source of 1,4-benzoquinone methide (from hydrogen peroxide oxidation
of a boronate substituted benzyl unit) and the second substituent group releasing
the ROS generator cinnamaldehyde on exposure to acidic conditions in the cancer
cell. The quinone methide would deplete the concentration of the natural oxidant
glutathione and overall an increase in oxidative stress results. Conceivably this
approach could be adapted to achieve multi-action antibacterial effects, perhaps
through enhancement of aPDT and using the sensitivity of aryl boronate esters to
hydrogen peroxide and the release of a benzoquinone methide intracellularly. Interestingly in this general context, reactive oxygen species also seem to be involved in the
antibacterial activity of two 1,4-benzoquinones isolated from an unusual source, the
venom of the scorpion Diplocentrus melici. These benzoquinones were found to have
good bactericidal activity against Staphylococcus aureus, and one of the componds,
6-methoxy-2,3-dithiomethyl-1,4-benzoquinone, also showed potent activity against
both drug-sensitive and drug resistant Mycobacterium tuberculosis both in vitro and
in vivo while apparently not damaging lung epithelia. Inititial results indicated this
compound acts through the generation of reactive oxygen species and subsequent
attack by these on a range of possible targets. These benzoquinones also interfered
with glutathione in a cell based assay (Carcamo-Noriega et al. 2019).
129
against strains of Acinetobacter baumannii which produce large quantities of the
lactamase ADC-1, as well as against Escherichia coli and Pseudomonas aeruginosa.
The siderophore-mediated active transport coupled with β-lactamase induced drug
release is a powerful combination for overcoming drug resistant bacteria. Replacement of the oxazolidinone with ester-linked ciprofloxacin, a strategy also used by
Evans et al. (2019), while retaining the attached siderophore moiety, is suggested to
be of interest as long as the ester linkage remains intact prior to active uptake of the
conjugate.
Targeted antibacterial delivery in an inactive enterobactin-ciprofloxacin conjugate
prodrug (Fig. 4.2) was achieved through the enterobactin siderophore uptake mechanism in an Escherichia coli pathogenic strain which expressed the iroA gene cluster.
After uptake, hydrolysis of the siderophore enterobactin moiety by a particular cytoplasmic hydrolase IroD in this strain then results in intracellular release of the active
antibacterial (Neumann et al. 2018). Such bacterial enzyme specificity could be used
as the basis for the development of narrow spectrum antibacterials.
Some antibiotics may also produce reactive oxygen species (ROSs) which could
complement other activity pathways, although this ROS proposal has been criticized
by others (Owens 2013). Interestingly hydrogen peroxide released by Streptococcus
pneumoniae inhibits inflammasomes resulting in immune suppression (Erttmann and
Gekara 2019). The bacteria avoid attack by the immune system, but how Streptococcus pneumoniae maintains high resistance itself to hydrogen peroxide is still
incompletely understood.
Reactive oxygen species could be useful, however, in triggering the release of
antibacterials in situ. In the anti-cancer context, Noh and co-workers reported on
the use of a hydrid drug responsive to dual stimuli which increased the death of
cancer cells via enhancement of oxidative stress (Noh et al. 2015). The hybrid
was based on a substituted carbonate diester moiety, with one substituent group
being the source of 1,4-benzoquinone methide (from hydrogen peroxide oxidation
of a boronate substituted benzyl unit) and the second substituent group releasing
the ROS generator cinnamaldehyde on exposure to acidic conditions in the cancer
cell. The quinone methide would deplete the concentration of the natural oxidant
glutathione and overall an increase in oxidative stress results. Conceivably this
approach could be adapted to achieve multi-action antibacterial effects, perhaps
through enhancement of aPDT and using the sensitivity of aryl boronate esters to
hydrogen peroxide and the release of a benzoquinone methide intracellularly. Interestingly in this general context, reactive oxygen species also seem to be involved in the
antibacterial activity of two 1,4-benzoquinones isolated from an unusual source, the
venom of the scorpion Diplocentrus melici. These benzoquinones were found to have
good bactericidal activity against Staphylococcus aureus, and one of the componds,
6-methoxy-2,3-dithiomethyl-1,4-benzoquinone, also showed potent activity against
both drug-sensitive and drug resistant Mycobacterium tuberculosis both in vitro and
in vivo while apparently not damaging lung epithelia. Inititial results indicated this
compound acts through the generation of reactive oxygen species and subsequent
attack by these on a range of possible targets. These benzoquinones also interfered
with glutathione in a cell based assay (Carcamo-Noriega et al. 2019).