3.3 Triple Action Antibacterial Hybrid Agents
83
action were displayed, one being induction of cell membrane permeability (from the
quaternary amino group functionalized side chain), the second being inhibition of
transpeptidase and cell wall biosynthesis (through dual D-Ala-D-Ala/D-Ala-D-Lac
binding with the carbonyl group change), and the third being inhibition of transglycolase and thus cell wall biosynthesis (from the sugar amino group modification).
Vancomycin analogues of this type showed a reduced susceptibility to acquired
resistance by vancomycin-resistant Enterococci.
Other multi-action and potent vancomycin derivatives have been described and
they involve functionalization at the vancomycin C-terminal through amide bond
formation. One such group are the vancapticins, which have a linker group to an
electrostatic peptide sequence (with positive charges for targeting and good interaction with the negatively charged phospholipid head groups in the bacterial lipid
bilayer) and a terminal lipophilic unit to enable insertion in the lipid bilayer. In
essence, one has a triple action mechanism operating with the third one being inhibition of transpeptidase and cell wall biosynthesis by the vancomycin core (Blaskovich
et al. 2018a).
Further vancomycin conjugates with at least a dual action and possibly more
have been described by Antonoplis et al. (2018). In these interesting and potent
compounds compounds, vancomycin was conjugated via an amide linkage again (at
the C-terminal carboxylic acid group and then a linker group) to D-octaarginine which
served as a transporter moiety to sterilize MRSA biofilms and eliminate persister
cells in vitro; this vancomycin conjugate also displayed excellent potency in vivo in
a biofilm-associated MRSA mouse model.
Cumbre Pharmaceutics introduced a rifamycin-4-oxoquinolizine hybrid antibiotic (CBR-2092) for Gram-negative infections which acts by interacting with and
inhibiting three targets: RNA polymerase, DNA gyrase and topoisomerase IV. CBR2092 was then developed by TenNor Therapeutics as TNP-2092 (Ma and Lynch 2016)
and has been granted FDA orphan drug status for the treatment of prosthetic joint
infections. These infections can be difficult to treat due to the formation of bacterial
biofilms. TNP-2092 (Fig. 3.16) has potent bactericidal activity against a range of
pathogens that are associated with such biofilms (Fisher et al. 2020), together with a
very good safety profile and a lower likelihood of resistance development as a result
of the multi-targeting. In addition TNP-2092 shows very good antibacterial activity
in vitro against clinical isolates of Helicobacter pylori, including strains with resistance to clarithromycin or levofloxacin (Ben et al. 2018). TNP-2092 also displayed
good activity in a mouse infection model of Clostridium difficile and oral TNP-2092
showed some changes, considered to be positive, in the rat gut microbiome (Yuan
et al. 2020b).
Compond TNP-2092 has a hydrazone unit linking the rifamycin and 4oxoquinolizine portions. This compound displayed unforeseen synergy both in vitro
and in vivo, compared to the separate drugs, but a query is whether it stays intact
in vivo or undergoes hydrolysis. While hyrazones are generally more stable to hydrolysis than imines they are still susceptible to hydrolysis under acidic conditions and
results suggestive of some hydrolysis is indicated in the work of Ben et al. (2018).
83
action were displayed, one being induction of cell membrane permeability (from the
quaternary amino group functionalized side chain), the second being inhibition of
transpeptidase and cell wall biosynthesis (through dual D-Ala-D-Ala/D-Ala-D-Lac
binding with the carbonyl group change), and the third being inhibition of transglycolase and thus cell wall biosynthesis (from the sugar amino group modification).
Vancomycin analogues of this type showed a reduced susceptibility to acquired
resistance by vancomycin-resistant Enterococci.
Other multi-action and potent vancomycin derivatives have been described and
they involve functionalization at the vancomycin C-terminal through amide bond
formation. One such group are the vancapticins, which have a linker group to an
electrostatic peptide sequence (with positive charges for targeting and good interaction with the negatively charged phospholipid head groups in the bacterial lipid
bilayer) and a terminal lipophilic unit to enable insertion in the lipid bilayer. In
essence, one has a triple action mechanism operating with the third one being inhibition of transpeptidase and cell wall biosynthesis by the vancomycin core (Blaskovich
et al. 2018a).
Further vancomycin conjugates with at least a dual action and possibly more
have been described by Antonoplis et al. (2018). In these interesting and potent
compounds compounds, vancomycin was conjugated via an amide linkage again (at
the C-terminal carboxylic acid group and then a linker group) to D-octaarginine which
served as a transporter moiety to sterilize MRSA biofilms and eliminate persister
cells in vitro; this vancomycin conjugate also displayed excellent potency in vivo in
a biofilm-associated MRSA mouse model.
Cumbre Pharmaceutics introduced a rifamycin-4-oxoquinolizine hybrid antibiotic (CBR-2092) for Gram-negative infections which acts by interacting with and
inhibiting three targets: RNA polymerase, DNA gyrase and topoisomerase IV. CBR2092 was then developed by TenNor Therapeutics as TNP-2092 (Ma and Lynch 2016)
and has been granted FDA orphan drug status for the treatment of prosthetic joint
infections. These infections can be difficult to treat due to the formation of bacterial
biofilms. TNP-2092 (Fig. 3.16) has potent bactericidal activity against a range of
pathogens that are associated with such biofilms (Fisher et al. 2020), together with a
very good safety profile and a lower likelihood of resistance development as a result
of the multi-targeting. In addition TNP-2092 shows very good antibacterial activity
in vitro against clinical isolates of Helicobacter pylori, including strains with resistance to clarithromycin or levofloxacin (Ben et al. 2018). TNP-2092 also displayed
good activity in a mouse infection model of Clostridium difficile and oral TNP-2092
showed some changes, considered to be positive, in the rat gut microbiome (Yuan
et al. 2020b).
Compond TNP-2092 has a hydrazone unit linking the rifamycin and 4oxoquinolizine portions. This compound displayed unforeseen synergy both in vitro
and in vivo, compared to the separate drugs, but a query is whether it stays intact
in vivo or undergoes hydrolysis. While hyrazones are generally more stable to hydrolysis than imines they are still susceptible to hydrolysis under acidic conditions and
results suggestive of some hydrolysis is indicated in the work of Ben et al. (2018).