2.1 Introduction
43
potentially ensue to manage these types of infections. The most effective combinations involved 5-aminolevulinic acid or phenothiazinium dyes in the aPDT with the
antibacterials administered post-aPDT consistent with PDT damage of the bacterial
cell wall or membrane then enabling increased penetration of the antibacterial agent
(Pérez-Laguna et al. 2019).
Instead of a combination approach, in other related work, a rose-bengalantimicrobial peptide conjugate (single molecule hybrid) which is activated by ultrasound (ROSs produced) was shown to be effective against Gram-negative and Grampositive bacteria (Costley et al. 2017). Extension of this to aPDT should also be
possible.
2.1.3.3 Type (II) Triple Combination (A − B) + C + D
In this combination, a dual action hybrid (A − B) or related prodrug plus two separate
compounds (C and D) could be used. A number of variations on this theme could be
envisaged including two dual acting hybrids and a third single component with one
further activity. No specific examples have been found in the literature but the type
is included to stimulate further consideration as a possible triple combination design
option for the future.
2.1.4 Quadruple Combinations with Four or More Actions
2.1.4.1 Type (I) Combination A + B + C + D
A recent paper by Yeh and co-workers (Tekin et al. 2018) reports on the discovery of
potent four (and five) antibacterial combinations against Escherichia coli. They used
eight antibiotics in the studies which had varying modes of action. These antibiotics
were ampicillin, cefoxitin sodium salt, trimethoprim, ciprofloxacin hydrochloride,
streptomycin, doxycycline hydrate, erythromycin and the sodium salt of fusidic acid.
Every possible four- and five- compound combination (a total of 18,278 combinations) including a significant number of combinations with varying dosages, were
assessed experimentally in vitro. All the two- and three-drug combinations were
tested as well. Surprisingly, a large number of four drug combinations (1676 out of
4007) were more effective than predicted on the independent individual antibiotic
effects in stopping the growth of Escherichia coli, while 6443 five-drug combinations
(out of 11,642) were more effective. An increased occurrence of emergent antagonism was also seen with the four or five way combinations. As noted by Coates
(2019) this type of work on antibacterial combinations has important implications
for future therapy. It is also important with regard to informing structural designs for
multi-active hybrids (or preferably prodrugs), but trying to incorporate four or five
separate activity capabilities in a single molecule has major challenges.
43
potentially ensue to manage these types of infections. The most effective combinations involved 5-aminolevulinic acid or phenothiazinium dyes in the aPDT with the
antibacterials administered post-aPDT consistent with PDT damage of the bacterial
cell wall or membrane then enabling increased penetration of the antibacterial agent
(Pérez-Laguna et al. 2019).
Instead of a combination approach, in other related work, a rose-bengalantimicrobial peptide conjugate (single molecule hybrid) which is activated by ultrasound (ROSs produced) was shown to be effective against Gram-negative and Grampositive bacteria (Costley et al. 2017). Extension of this to aPDT should also be
possible.
2.1.3.3 Type (II) Triple Combination (A − B) + C + D
In this combination, a dual action hybrid (A − B) or related prodrug plus two separate
compounds (C and D) could be used. A number of variations on this theme could be
envisaged including two dual acting hybrids and a third single component with one
further activity. No specific examples have been found in the literature but the type
is included to stimulate further consideration as a possible triple combination design
option for the future.
2.1.4 Quadruple Combinations with Four or More Actions
2.1.4.1 Type (I) Combination A + B + C + D
A recent paper by Yeh and co-workers (Tekin et al. 2018) reports on the discovery of
potent four (and five) antibacterial combinations against Escherichia coli. They used
eight antibiotics in the studies which had varying modes of action. These antibiotics
were ampicillin, cefoxitin sodium salt, trimethoprim, ciprofloxacin hydrochloride,
streptomycin, doxycycline hydrate, erythromycin and the sodium salt of fusidic acid.
Every possible four- and five- compound combination (a total of 18,278 combinations) including a significant number of combinations with varying dosages, were
assessed experimentally in vitro. All the two- and three-drug combinations were
tested as well. Surprisingly, a large number of four drug combinations (1676 out of
4007) were more effective than predicted on the independent individual antibiotic
effects in stopping the growth of Escherichia coli, while 6443 five-drug combinations
(out of 11,642) were more effective. An increased occurrence of emergent antagonism was also seen with the four or five way combinations. As noted by Coates
(2019) this type of work on antibacterial combinations has important implications
for future therapy. It is also important with regard to informing structural designs for
multi-active hybrids (or preferably prodrugs), but trying to incorporate four or five
separate activity capabilities in a single molecule has major challenges.