10
1 Antibacterials
exposure to an antibacterial agent (Borges et al. 2015). Ways to disperse biofilms
and expose the bacteria to antibacterials is an important area of current research.
Another bacterial survival strategy is that of programmed cell death in bacterial
communities which results in the death of some bacteria to ensure the survival of
the greater population (Peeters and de Jonge 2018; Tanouchi et al. 2013); see also
Sect. 5.4 in Chap. 5. While it is an advantageous strategy, it may also open up a
potential bacterial vulnerability in which unprogrammed, or premature, cell death
might be initiated via small molecule interventions, which could be detrimental.
Careful structural design work would be required for such small molecules but it is
considered worth pursuing. To inform the design work one might search initially for
endogenous molecules in bacteria which sense premature bacterial cell death and
which then initiate other actions to locate and nullify the problem. Interference with
the actions of any such molecules, if identified, would then need to be factored in to
the design process.
1.4 Approaches to Meeting Needs
Although many lines of enquiry aimed at countering human bacterial disease threats
are now being pursued (Thayer 2016; Brown and Wright 2016), additional radical
ideas and new approaches are required, as well as improvements on current treatments. For example, the disease induced by Clostridiodes difficile is a major health
care threat in the US (CDC 2019) and elsewhere, and although it is not related to
antibiotic resistance acquisition, there is a compelling need for bacterially selective
therapeutics for this pathogen (CDC 2019).
Approaches to meeting such needs cover a number of broad strategic categories
including the following: theranostics (a combination of therapeutics and diagnostics); rational improvement of existing antibiotics; remedying the liabilities of old
antibiotics; and looking for new antibacterials with different structures and preferably different modes of action (Cooper 2018). Approaches in the last category can
include screening the chemically diverse global compound libraries for example
via the Community for Open Antimicrobial Drug Discovery (CoADD) (Blaskovich
2016) and through looking at new natural product sources, as well as devising and
implementing new molecular designs.
A good example of liability repair is the replacement of a secondary hydroxyl
group by a fluoro group in the aminoglycoside, neomycin B, an old antibiotic, but
one now susceptible to aminoglycoside-modifying enzymes which acetylate amino
groups and phosphorylate hydroxyl groups. Such modifications compromise potency
through consequent changes in polarity and thus cell penetration. A series of 4
-
deoxy-4
-fluoro neomycin analogues were made with improved resistant enzyme
inhibition profiles while retaining good antibacterial potency in vitro (Hanessian
et al. 2014). An interesting variation on substituent variation to improve potency also
involves the neomycin template and attachment of a catalytic diamino alkyl group via
a 4
-ether linkage at one of the terminal sugar units. After binding of the neomycin
1 Antibacterials
exposure to an antibacterial agent (Borges et al. 2015). Ways to disperse biofilms
and expose the bacteria to antibacterials is an important area of current research.
Another bacterial survival strategy is that of programmed cell death in bacterial
communities which results in the death of some bacteria to ensure the survival of
the greater population (Peeters and de Jonge 2018; Tanouchi et al. 2013); see also
Sect. 5.4 in Chap. 5. While it is an advantageous strategy, it may also open up a
potential bacterial vulnerability in which unprogrammed, or premature, cell death
might be initiated via small molecule interventions, which could be detrimental.
Careful structural design work would be required for such small molecules but it is
considered worth pursuing. To inform the design work one might search initially for
endogenous molecules in bacteria which sense premature bacterial cell death and
which then initiate other actions to locate and nullify the problem. Interference with
the actions of any such molecules, if identified, would then need to be factored in to
the design process.
1.4 Approaches to Meeting Needs
Although many lines of enquiry aimed at countering human bacterial disease threats
are now being pursued (Thayer 2016; Brown and Wright 2016), additional radical
ideas and new approaches are required, as well as improvements on current treatments. For example, the disease induced by Clostridiodes difficile is a major health
care threat in the US (CDC 2019) and elsewhere, and although it is not related to
antibiotic resistance acquisition, there is a compelling need for bacterially selective
therapeutics for this pathogen (CDC 2019).
Approaches to meeting such needs cover a number of broad strategic categories
including the following: theranostics (a combination of therapeutics and diagnostics); rational improvement of existing antibiotics; remedying the liabilities of old
antibiotics; and looking for new antibacterials with different structures and preferably different modes of action (Cooper 2018). Approaches in the last category can
include screening the chemically diverse global compound libraries for example
via the Community for Open Antimicrobial Drug Discovery (CoADD) (Blaskovich
2016) and through looking at new natural product sources, as well as devising and
implementing new molecular designs.
A good example of liability repair is the replacement of a secondary hydroxyl
group by a fluoro group in the aminoglycoside, neomycin B, an old antibiotic, but
one now susceptible to aminoglycoside-modifying enzymes which acetylate amino
groups and phosphorylate hydroxyl groups. Such modifications compromise potency
through consequent changes in polarity and thus cell penetration. A series of 4
-
deoxy-4
-fluoro neomycin analogues were made with improved resistant enzyme
inhibition profiles while retaining good antibacterial potency in vitro (Hanessian
et al. 2014). An interesting variation on substituent variation to improve potency also
involves the neomycin template and attachment of a catalytic diamino alkyl group via
a 4
-ether linkage at one of the terminal sugar units. After binding of the neomycin