32
2 Antibacterial Combinations
2.1.2.2 Dual Action Hybrid Agent (A − B) Plus Another Agent (C)
While administering three separate drugs each with a different mode of action can
be an effective treatment regime especially where high target doses are required, a
potentially viable alternative is to reduce the number of drugs in the combination to
two but have one as a hybrid with two mechanisms of action and the other drug with
just one action or even more than one. In this way one could have a dual molecular
combination of two separate drugs with three, or potentially more, actions. Expressions of this design principle could include perhaps a hybrid peptide (Jindal et al.
2017) plus ceftriaxone, or erythromycin. Other possibilities have also been described
including the use of hybrid adjuvants, for instance a tobramycin-ciprofloxacin hybrid
compound synergising with mitomycin C as discussed by Domalaon et al. (2019) or of
a nebramine-cyclam hybrid conjugate potentiating β-lactam antibiotics in multidrugresistant Pseudomonas aeruginosa (Ammeter et al. 2019). Further studies in this
area by the same group now include other nebramine-fluoroquinolone hybrids and
an NMP-linked hybrid (NMP, 1-(1-naphthylmethyl)-piperazine, is an efflux pump
inhibitor), as described by Yang et al. (2019). Incorporating a hybrid with one other
drug in a dual combination could be beneficial in helping to reduce pharmacokinetic
issues that might present in vivo with a combination of deconstructed components.
Two-pronged actions at the one site also have potential for new antibacterial
design. For example one action could involve specific binding to a biological protein
target through non-covalent interactions, but through this interaction favourably
dispose a ‘warhead’ moiety for further covalent bonding involving a neighbouring
amino acid residue site with a reactive side-chain like cysteine or serine (Brown
and Boström 2018). This strategy has been used to reinforce binding and heighten
potency in the oncology therapeutic area with Janus kinase (JAK) inhibitors and
should also be transferable to potential bacterial targets as long as selective, but care
would be needed. In the antibacterial context, another dual combination possibility
would be to incorporate in a single inhibitor molecule bitopic binding to an efflux
pump plus an antibiotic with more than one action.
The question arises whether there any examples in Nature of the above dual
combination type (A − B) plus (C)? It is not inconceivable that bacteria might produce
a dual action antibacterial plus an efflux pump inhibitor as a sophisticated defence
against competitive bacteria. This may seem unusual but perhaps the bacterially
produced efflux pump inhibitors could be sequestered in some way and then released
externally when required together with the antibiotic produced by the bacterium. The
production of antibiotics by bacteria is well established as is their use as a weapon
against other bacteria in the soil environment; increased antibiotic production has also
been noted when there were neighbouring competing bacterial strains (Abrudan et al.
2015). There appears to be no studies reported on possible bacterial co-production
of efflux pump modulators and it may be difficult to locate such bacterial producers.
Does this occur for example in maintaining a healthy human microbiome with a
host plus a bacterial molecular component? Further investigation to try and answer
this question would seem warranted. Also of some possible relevance is the fact that
2 Antibacterial Combinations
2.1.2.2 Dual Action Hybrid Agent (A − B) Plus Another Agent (C)
While administering three separate drugs each with a different mode of action can
be an effective treatment regime especially where high target doses are required, a
potentially viable alternative is to reduce the number of drugs in the combination to
two but have one as a hybrid with two mechanisms of action and the other drug with
just one action or even more than one. In this way one could have a dual molecular
combination of two separate drugs with three, or potentially more, actions. Expressions of this design principle could include perhaps a hybrid peptide (Jindal et al.
2017) plus ceftriaxone, or erythromycin. Other possibilities have also been described
including the use of hybrid adjuvants, for instance a tobramycin-ciprofloxacin hybrid
compound synergising with mitomycin C as discussed by Domalaon et al. (2019) or of
a nebramine-cyclam hybrid conjugate potentiating β-lactam antibiotics in multidrugresistant Pseudomonas aeruginosa (Ammeter et al. 2019). Further studies in this
area by the same group now include other nebramine-fluoroquinolone hybrids and
an NMP-linked hybrid (NMP, 1-(1-naphthylmethyl)-piperazine, is an efflux pump
inhibitor), as described by Yang et al. (2019). Incorporating a hybrid with one other
drug in a dual combination could be beneficial in helping to reduce pharmacokinetic
issues that might present in vivo with a combination of deconstructed components.
Two-pronged actions at the one site also have potential for new antibacterial
design. For example one action could involve specific binding to a biological protein
target through non-covalent interactions, but through this interaction favourably
dispose a ‘warhead’ moiety for further covalent bonding involving a neighbouring
amino acid residue site with a reactive side-chain like cysteine or serine (Brown
and Boström 2018). This strategy has been used to reinforce binding and heighten
potency in the oncology therapeutic area with Janus kinase (JAK) inhibitors and
should also be transferable to potential bacterial targets as long as selective, but care
would be needed. In the antibacterial context, another dual combination possibility
would be to incorporate in a single inhibitor molecule bitopic binding to an efflux
pump plus an antibiotic with more than one action.
The question arises whether there any examples in Nature of the above dual
combination type (A − B) plus (C)? It is not inconceivable that bacteria might produce
a dual action antibacterial plus an efflux pump inhibitor as a sophisticated defence
against competitive bacteria. This may seem unusual but perhaps the bacterially
produced efflux pump inhibitors could be sequestered in some way and then released
externally when required together with the antibiotic produced by the bacterium. The
production of antibiotics by bacteria is well established as is their use as a weapon
against other bacteria in the soil environment; increased antibiotic production has also
been noted when there were neighbouring competing bacterial strains (Abrudan et al.
2015). There appears to be no studies reported on possible bacterial co-production
of efflux pump modulators and it may be difficult to locate such bacterial producers.
Does this occur for example in maintaining a healthy human microbiome with a
host plus a bacterial molecular component? Further investigation to try and answer
this question would seem warranted. Also of some possible relevance is the fact that