54
3 Single Molecule Non-cleavable Multiply Active Antibacterials
Further factors require attention at the in vivo level and encompass oral vs intravenous administration; oral administration-stability to acidic pH, effect on the microbiome; ADME characteristics; other chemical transformations; then concentration
at the bacterial site followed by the considerations delineated at the cell level in vitro.
Clinical consequences after bacterial killing are also important but are not within the
scope of this book.
In assessing ADME factors, ways to administer antibacterials, including unusual
ones, are also important considerations and can have a major bearing on their effectiveness. Normally oral or intravenous administration methods are employed, while
topical administration is used for bacterial skin infections, and suppositories can
also be employed for other applications. For lung infections administration of the
antibacterial through inhalation is an effective approach which bypasses exposure of
the drug to the gut microflora and also high serum levels thus minimising off target
effects. This pulmonary antibacterial delivery area and the associated difficulties
with formulation has been well reviewed recently (Woods and Rahman 2018). For
brain bacterial infections, the Blood Brain Barrier poses a significant drug delivery
challenge, but perhaps nose-to-brain delivery might continue to be developed while
taking into account other serious issues for such direct delivery (Schwarz and Merkel
2019).
A number of rules or guidelines have been developed to help with the design and
development of new drugs including Lipinski’s rule of five for oral bioavailability,
structural features for oral administration and systemic absorption beyond the rule
of five, and guidelines for permeation or penetration of Gram-negative pathogens.
Aspects of the last two areas are discussed further in the following paragraphs.
From a retrospective analysis, DeGoey and co-workers (DeGoey et al. 2018)
derived a relatively simple multiparametric scoring (MPS) function for orally
bioavailable drugs beyond the rule of five as elaborated by Lipinsky. This function,
formulated as AB-MPS = Abs(clogD-3) + NAR + NRB, correlated pre-clinical PK
results of drugs and compounds in the collection of the American biopharmaceutical company AbbVie Inc.(AB), with Abs(cLogD-3), the number of aromatic rings
(NAR), and the number of rotatable bonds (NRB) in the compound. Values of ABMPS less than or equal to 14 were indicative of reasonable levels of oral absorption
for compounds beyond the rule of five. Recognition that molecules are generally not
rigid or inflexible entities is also important and further developments in this area
cover this more explicitly looking at the effect of dynamically exposed polarity on
solubility and permeability of chameleonic or adaptive drugs not compliant with the
Rule of 5 (Sebastiano et al. 2018). Ways to quantify these chameleonic properties in
macrocyclic drugs have been discussed by Whitty et al. (2016).
The recently developed structural guidelines for permeation of Gram-negative
pathogens have been introduced in Chap. 1 (Sect. 1.3.3) and further detail is given
here. These predictive compound accumulation or penetration rules in Escherichia
coli were elaborated by the Hergenrother group (Parker et al. 2020; Richter et al.
2017). Surprisingly, compounds most likely to accumulate contain a sterically lesshindered (primary) amino group, are amphiphilic and rigid, and have low globularity
(Richter et al. 2017). The Hergenrother group have also reported on the application
3 Single Molecule Non-cleavable Multiply Active Antibacterials
Further factors require attention at the in vivo level and encompass oral vs intravenous administration; oral administration-stability to acidic pH, effect on the microbiome; ADME characteristics; other chemical transformations; then concentration
at the bacterial site followed by the considerations delineated at the cell level in vitro.
Clinical consequences after bacterial killing are also important but are not within the
scope of this book.
In assessing ADME factors, ways to administer antibacterials, including unusual
ones, are also important considerations and can have a major bearing on their effectiveness. Normally oral or intravenous administration methods are employed, while
topical administration is used for bacterial skin infections, and suppositories can
also be employed for other applications. For lung infections administration of the
antibacterial through inhalation is an effective approach which bypasses exposure of
the drug to the gut microflora and also high serum levels thus minimising off target
effects. This pulmonary antibacterial delivery area and the associated difficulties
with formulation has been well reviewed recently (Woods and Rahman 2018). For
brain bacterial infections, the Blood Brain Barrier poses a significant drug delivery
challenge, but perhaps nose-to-brain delivery might continue to be developed while
taking into account other serious issues for such direct delivery (Schwarz and Merkel
2019).
A number of rules or guidelines have been developed to help with the design and
development of new drugs including Lipinski’s rule of five for oral bioavailability,
structural features for oral administration and systemic absorption beyond the rule
of five, and guidelines for permeation or penetration of Gram-negative pathogens.
Aspects of the last two areas are discussed further in the following paragraphs.
From a retrospective analysis, DeGoey and co-workers (DeGoey et al. 2018)
derived a relatively simple multiparametric scoring (MPS) function for orally
bioavailable drugs beyond the rule of five as elaborated by Lipinsky. This function,
formulated as AB-MPS = Abs(clogD-3) + NAR + NRB, correlated pre-clinical PK
results of drugs and compounds in the collection of the American biopharmaceutical company AbbVie Inc.(AB), with Abs(cLogD-3), the number of aromatic rings
(NAR), and the number of rotatable bonds (NRB) in the compound. Values of ABMPS less than or equal to 14 were indicative of reasonable levels of oral absorption
for compounds beyond the rule of five. Recognition that molecules are generally not
rigid or inflexible entities is also important and further developments in this area
cover this more explicitly looking at the effect of dynamically exposed polarity on
solubility and permeability of chameleonic or adaptive drugs not compliant with the
Rule of 5 (Sebastiano et al. 2018). Ways to quantify these chameleonic properties in
macrocyclic drugs have been discussed by Whitty et al. (2016).
The recently developed structural guidelines for permeation of Gram-negative
pathogens have been introduced in Chap. 1 (Sect. 1.3.3) and further detail is given
here. These predictive compound accumulation or penetration rules in Escherichia
coli were elaborated by the Hergenrother group (Parker et al. 2020; Richter et al.
2017). Surprisingly, compounds most likely to accumulate contain a sterically lesshindered (primary) amino group, are amphiphilic and rigid, and have low globularity
(Richter et al. 2017). The Hergenrother group have also reported on the application