4.4 Metabolism Activated Multi-targeting
151
a prodrug is not specifically involved initially they are presumably involved as intermediates on the steps through to oxaprozin. MAMUT is related through ultimate
outcomes to the bioprecursor prodrug classification but is precluded from this classification since, formally, a prodrug is not active until activated. In nature, metabolic
activation to give an active multi-targeting antibacterial from a precursor can also
occur as exemplified by the lantibiotic lacticin 481. This antibiotic, which is produced
by some strains of the Gram-positive bacterium Lactococcus lactis, arises from
a ribosomally-produced prepeptide which is then post-translationally modified by
the enzyme lantibiotic synthetase (LctM) in two stages and finally released after
proteolytic cleavage of a leader peptide unit (Xie et al. 2004).
In applying the MAMUT approach in the multi-action antibacterial context one
would need to look for a suitably functionalized antibacterial molecule, perhaps a
natural product (Ho et al. 2018), with a metabolically sensitive functional group
or moiety whose likely metabolites might potentiate the action of the starting drug
by interacting with another target or targets. If the metabolic transformation was
unique to the bacterium this would be a further plus. This could be quite difficult
to achieve in molecular terms but not impossible. One could consider for example a
starting compound such as the N-formyl structure (Scheme 4.8a), which could have
multi-activity. If the starting material was also bioactive then it falls under MAMUT.
Metabolism of the terminal N-formamide moiety by bacterial peptide deformylase
could conceivably generate a primary amino group which might then internally
displace a group C
with one activity and a cyclic hybrid product (Scheme 4.8b)
with a pendant A-B group capable of interacting with two other target sites either
on the one macromolecule or at one site each on two different macromolecules.
Product C
might be a monobactam or contain a pharmacophoric unit which could
inhibit another aspect of bacterial protein synthesis. Apart from designing for synergistic interactions, considerations would need to include the rate of hydrolysis of
N-formamides independent of peptide deformylase. Such hydrolysis would need to
be very slow.
4.5 Conclusion
Both carrier-linked and bioprecursor prodrugs have been developed for release of
compounds with multi-targeting capability in the antibacterial area. Various designs
and triggering mechanisms have been assessed but there is much more scope
for new prodrugs with better selectivity and different release strategies. Particular
emphasis on releasing multi-active hybrid compounds as well as multi-active gaseous
molecules should be prioritised in future research.
The ultimate goal would be to design and develop orally bioavailable, targeted
Gram-negative and Gram-positive penetrant prodrugs as precursors for multitargeting agents active against both resistant and non-resistant strains and with a
low propensity for resistance development. This is a major challenge which might
best be met by focussing on separate sub-categories of compounds with perhaps
151
a prodrug is not specifically involved initially they are presumably involved as intermediates on the steps through to oxaprozin. MAMUT is related through ultimate
outcomes to the bioprecursor prodrug classification but is precluded from this classification since, formally, a prodrug is not active until activated. In nature, metabolic
activation to give an active multi-targeting antibacterial from a precursor can also
occur as exemplified by the lantibiotic lacticin 481. This antibiotic, which is produced
by some strains of the Gram-positive bacterium Lactococcus lactis, arises from
a ribosomally-produced prepeptide which is then post-translationally modified by
the enzyme lantibiotic synthetase (LctM) in two stages and finally released after
proteolytic cleavage of a leader peptide unit (Xie et al. 2004).
In applying the MAMUT approach in the multi-action antibacterial context one
would need to look for a suitably functionalized antibacterial molecule, perhaps a
natural product (Ho et al. 2018), with a metabolically sensitive functional group
or moiety whose likely metabolites might potentiate the action of the starting drug
by interacting with another target or targets. If the metabolic transformation was
unique to the bacterium this would be a further plus. This could be quite difficult
to achieve in molecular terms but not impossible. One could consider for example a
starting compound such as the N-formyl structure (Scheme 4.8a), which could have
multi-activity. If the starting material was also bioactive then it falls under MAMUT.
Metabolism of the terminal N-formamide moiety by bacterial peptide deformylase
could conceivably generate a primary amino group which might then internally
displace a group C
with one activity and a cyclic hybrid product (Scheme 4.8b)
with a pendant A-B group capable of interacting with two other target sites either
on the one macromolecule or at one site each on two different macromolecules.
Product C
might be a monobactam or contain a pharmacophoric unit which could
inhibit another aspect of bacterial protein synthesis. Apart from designing for synergistic interactions, considerations would need to include the rate of hydrolysis of
N-formamides independent of peptide deformylase. Such hydrolysis would need to
be very slow.
4.5 Conclusion
Both carrier-linked and bioprecursor prodrugs have been developed for release of
compounds with multi-targeting capability in the antibacterial area. Various designs
and triggering mechanisms have been assessed but there is much more scope
for new prodrugs with better selectivity and different release strategies. Particular
emphasis on releasing multi-active hybrid compounds as well as multi-active gaseous
molecules should be prioritised in future research.
The ultimate goal would be to design and develop orally bioavailable, targeted
Gram-negative and Gram-positive penetrant prodrugs as precursors for multitargeting agents active against both resistant and non-resistant strains and with a
low propensity for resistance development. This is a major challenge which might
best be met by focussing on separate sub-categories of compounds with perhaps