22
2 Antibacterial Combinations
on the potential ability of their component compounds to access a range of targets
simultaneously or near simultaneously in contrast to a compound interacting just
with a single target, rendering such single compounds more susceptible to resistance
development. As well as this, the recognition of effective drug combinations can
provide a powerful starting point for single molecule hybrid or prodrug design with
potential benefits over the combinations.
Synergistic, additive or antagonistic interactions may occur with combinations.
These interactions can be complex and a thorough analysis with respect to drug
combinations in general and network perspectives is given in the review by Jia et al.
(2009) and in a perspectives article by Chou (2010), who highlights the issues with
combination studies.
It is important to note that combinations are not always beneficial and antagonism has been noted between bacteriostatic and bactericidal agents in pairwise drug
combinations using 21 different antibiotics at sub-inhibitory concentrations in vitro
(Ocampo et al. 2014) and it is not inconceivable that antagonism may be possible
with triple and greater combinations. Paradoxically, antagonism may be better though
at slowing resistance development. Although it is generally the case that development of resistance may be reduced with combinations it is not always the case. It
has been shown that not all synergistic combinations show clinical benefit and in a
number of instances do not always slow resistance development. In a later interesting
study on species-specific drug combinations, Brochado et al. (2018) looked at nearly
3000 pair-wise combinations of antibiotics, human-targeted drugs and food additives and their effects on three Gram-negative pathogens, namely Escherichia coli,
Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa (a total
of six strains from these three pathogens). More than 70% of the identified drugdrug interactions were species specific and some 20% showed strain specificity.
Also, significantly, antagonistic interactions were observed more frequently than
synergistic ones with the former appearing almost always between drugs targeting
different cellular processes in contrast to the latter which were manifested more when
the same cellular process was being targeted. This clearly has implications for the
design of new multi-targeting combinations.
While the main focus of this book is on ways to achieve more than two actions,
looking at dual action drug combinations to start with can provide a useful platform
from which to extend to multiply active combinations or the design of new multiply
active hybrid molecules or related prodrugs.
In this chapter the classification of the materials is primarily based on the number
of separate components in the combinations with sub-sections based on the number
of resulting actions or interactions with the bacterial targets or the way in which
components might be activated. The actions themselves may be directly antibacterial or they may potentiate this activity through other actions i.e. the component
is viewed as indirectly antibacterial. Worthington and Melander (2013) have noted
three activity-type categories in antibiotic combinations based on targets and pathways and they also discuss antibiotic with adjuvant combinations. These areas are
also covered in the subsequent sections.
2 Antibacterial Combinations
on the potential ability of their component compounds to access a range of targets
simultaneously or near simultaneously in contrast to a compound interacting just
with a single target, rendering such single compounds more susceptible to resistance
development. As well as this, the recognition of effective drug combinations can
provide a powerful starting point for single molecule hybrid or prodrug design with
potential benefits over the combinations.
Synergistic, additive or antagonistic interactions may occur with combinations.
These interactions can be complex and a thorough analysis with respect to drug
combinations in general and network perspectives is given in the review by Jia et al.
(2009) and in a perspectives article by Chou (2010), who highlights the issues with
combination studies.
It is important to note that combinations are not always beneficial and antagonism has been noted between bacteriostatic and bactericidal agents in pairwise drug
combinations using 21 different antibiotics at sub-inhibitory concentrations in vitro
(Ocampo et al. 2014) and it is not inconceivable that antagonism may be possible
with triple and greater combinations. Paradoxically, antagonism may be better though
at slowing resistance development. Although it is generally the case that development of resistance may be reduced with combinations it is not always the case. It
has been shown that not all synergistic combinations show clinical benefit and in a
number of instances do not always slow resistance development. In a later interesting
study on species-specific drug combinations, Brochado et al. (2018) looked at nearly
3000 pair-wise combinations of antibiotics, human-targeted drugs and food additives and their effects on three Gram-negative pathogens, namely Escherichia coli,
Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa (a total
of six strains from these three pathogens). More than 70% of the identified drugdrug interactions were species specific and some 20% showed strain specificity.
Also, significantly, antagonistic interactions were observed more frequently than
synergistic ones with the former appearing almost always between drugs targeting
different cellular processes in contrast to the latter which were manifested more when
the same cellular process was being targeted. This clearly has implications for the
design of new multi-targeting combinations.
While the main focus of this book is on ways to achieve more than two actions,
looking at dual action drug combinations to start with can provide a useful platform
from which to extend to multiply active combinations or the design of new multiply
active hybrid molecules or related prodrugs.
In this chapter the classification of the materials is primarily based on the number
of separate components in the combinations with sub-sections based on the number
of resulting actions or interactions with the bacterial targets or the way in which
components might be activated. The actions themselves may be directly antibacterial or they may potentiate this activity through other actions i.e. the component
is viewed as indirectly antibacterial. Worthington and Melander (2013) have noted
three activity-type categories in antibiotic combinations based on targets and pathways and they also discuss antibiotic with adjuvant combinations. These areas are
also covered in the subsequent sections.