144
4 Design Principles and Development of Prodrugs for Multiply …
Scheme 4.6 Suggested reaction scheme for the release of antibacterial components by nitroreductase
Fig. 4.6 Structure of the
prodrug pretomanid
drug released inhibits cell wall mycolic acid biosynthesis and also furnishes nitric
oxide which can poison the respiratory chain. While the NO mechanism of action here
is not fully resolved it is likely to be multidimensional. Details on the proposed NO
producing mechanism are given in the paper by Thompson et al. (2017) which deals
with anti-TB bicyclic nitroimidazoles. Pretomanid, in combination with bedaquiline
and linezolid, was approved by the FDA in August 2019 for the treatment of a specific
type of pulmonary tuberculosis which is highly resistant to treatment.
The use of a β-lactamase as a trigger for prodrug activation and drug release
continues to be widely investigated. Work recently reported by Evans et al. (2019)
(see also Sect. 4.2.2 in this chapter) covers refinement of the β-lactamase induced
release of ciprofloxacin from an ester linked conjugate. The difference from previous
compounds of this type is that the prodrug is designed to have no or little inherent
antibacterial activity and would thus not release the ciprofloxacin until exposed to
lactamase producing pathogens. Activity similar to ciprofloxacin itself was seen
with an Escherichia coli isolate expressing β-lactamases. Such selectively activated
prodrugs have potential clinical advantages in terms of less broad brush disruption
to microbiota and reducing selection for resistance pressures. This prodrug approach
may also help to obviate the severely detrimental toxic effects of ciprofloxacin (and
other fluoroquinolones) seen in a small percentage of the population systemically
exposed to fluoroquinolone antibacterials in the treatment of bacterial infections
(Marchant 2018).
Non-β-lactams working somewhat like a β-lactam have been developed and these,
like avibactam, react reversibly with some serine β-lactamases (Wang et al. 2016).
4 Design Principles and Development of Prodrugs for Multiply …
Scheme 4.6 Suggested reaction scheme for the release of antibacterial components by nitroreductase
Fig. 4.6 Structure of the
prodrug pretomanid
drug released inhibits cell wall mycolic acid biosynthesis and also furnishes nitric
oxide which can poison the respiratory chain. While the NO mechanism of action here
is not fully resolved it is likely to be multidimensional. Details on the proposed NO
producing mechanism are given in the paper by Thompson et al. (2017) which deals
with anti-TB bicyclic nitroimidazoles. Pretomanid, in combination with bedaquiline
and linezolid, was approved by the FDA in August 2019 for the treatment of a specific
type of pulmonary tuberculosis which is highly resistant to treatment.
The use of a β-lactamase as a trigger for prodrug activation and drug release
continues to be widely investigated. Work recently reported by Evans et al. (2019)
(see also Sect. 4.2.2 in this chapter) covers refinement of the β-lactamase induced
release of ciprofloxacin from an ester linked conjugate. The difference from previous
compounds of this type is that the prodrug is designed to have no or little inherent
antibacterial activity and would thus not release the ciprofloxacin until exposed to
lactamase producing pathogens. Activity similar to ciprofloxacin itself was seen
with an Escherichia coli isolate expressing β-lactamases. Such selectively activated
prodrugs have potential clinical advantages in terms of less broad brush disruption
to microbiota and reducing selection for resistance pressures. This prodrug approach
may also help to obviate the severely detrimental toxic effects of ciprofloxacin (and
other fluoroquinolones) seen in a small percentage of the population systemically
exposed to fluoroquinolone antibacterials in the treatment of bacterial infections
(Marchant 2018).
Non-β-lactams working somewhat like a β-lactam have been developed and these,
like avibactam, react reversibly with some serine β-lactamases (Wang et al. 2016).