1.3 Bacterial Resistance to Antibacterials
9
non-polar structural features, molecular rigidity (few rotatable bonds) and low globularity. It was also shown that by including a primary aminomethylene substituent
group in the DNA gyrase inhibitor, deoxynybomycin, it increased it’s intracellular
accumulation over three fold and antibacterial potency in vitro against a range of
laboratory and clinical Escherichia coli strains, as well as against strains of Acinetobacter baumanii, Klebsiella pneumoniae, Enterobacter cloaca, and against Pseudomonas aeruginosa. In a number of cases the potency shown was better than that
of the control, ciprofloxacin. Interestingly, strong activity was also seen against two
strains of the Gram-positive pathogen Staphylococcus aureus (Richter et al. 2017).
Further discussion of the new rules for Gram-negative penetration is given in Chap. 3,
Sect. 3.1.2.
1.3.4 Other Survival Strategies
Another protective mechanism is associated with responses by bacteria to stress,
including assault by antibiotics, which can involve adaptive changes like going into
‘dormancy’ for the time of exposure to an antibiotic then re-growing when exposure
is stopped after antibiotic removal. This is a tolerance strategy which enables bacterial survival, as long as the exposure to the antibiotic is not too prolonged (Fridman
et al. 2014). The mechanisms of collective antibiotic tolerance and possible intervention strategies have been elaborated in a good article by Meredith et al. (2015).
Further study to determine what sensors are involved in triggering tolerance could
potentially be useful in informing the design of other potential multi-targeted ligands
which might interfere with any signalling process or processes involved. While not
impossible, it will be challenging to design agents to overcome antibiotic tolerance
in tackling resistance and it will be important in antibacterial screening methodology
to include drug-tolerant bacteria (Stokes et al. 2019).
Further resistance is manifested in slow growing bacteria through the expression
of persister cells (Kåhström 2014) and also with the formation of spores which can
be hard to counter. Sporolation can complicate the treatment of chronic bacterial
infections as is the case with Clostridium difficile (Jarrad et al. 2015).
Bacterial persistence is defined as the development of antibiotic-tolerant slowgrowing persister cells as a sub-population within the bacterial population resulting
in difficulties with responses to antibiotic treatments and a biphasic killing curve
(Carvalho et al. 2019). Interestingly, another phenotypic response which seems to
be related to, but not the same as, persistence in some ways is that identified as the
Eagle Effect in which bacteria can have a higher level of survival when exposed
to antibacterial drug concentrations at higher levels than an optimal bactericidal
concentration. Under these conditions there is a net decrease in the rate of cell death
(Prasetyoputri et al. 2019).
An important and highly problematic further bacterial protective mechanism is
that of biofilm formation. This involves a multistep process and the ultimate protection of bacteria on surfaces by a covering layer which generally provides a shield from
9
non-polar structural features, molecular rigidity (few rotatable bonds) and low globularity. It was also shown that by including a primary aminomethylene substituent
group in the DNA gyrase inhibitor, deoxynybomycin, it increased it’s intracellular
accumulation over three fold and antibacterial potency in vitro against a range of
laboratory and clinical Escherichia coli strains, as well as against strains of Acinetobacter baumanii, Klebsiella pneumoniae, Enterobacter cloaca, and against Pseudomonas aeruginosa. In a number of cases the potency shown was better than that
of the control, ciprofloxacin. Interestingly, strong activity was also seen against two
strains of the Gram-positive pathogen Staphylococcus aureus (Richter et al. 2017).
Further discussion of the new rules for Gram-negative penetration is given in Chap. 3,
Sect. 3.1.2.
1.3.4 Other Survival Strategies
Another protective mechanism is associated with responses by bacteria to stress,
including assault by antibiotics, which can involve adaptive changes like going into
‘dormancy’ for the time of exposure to an antibiotic then re-growing when exposure
is stopped after antibiotic removal. This is a tolerance strategy which enables bacterial survival, as long as the exposure to the antibiotic is not too prolonged (Fridman
et al. 2014). The mechanisms of collective antibiotic tolerance and possible intervention strategies have been elaborated in a good article by Meredith et al. (2015).
Further study to determine what sensors are involved in triggering tolerance could
potentially be useful in informing the design of other potential multi-targeted ligands
which might interfere with any signalling process or processes involved. While not
impossible, it will be challenging to design agents to overcome antibiotic tolerance
in tackling resistance and it will be important in antibacterial screening methodology
to include drug-tolerant bacteria (Stokes et al. 2019).
Further resistance is manifested in slow growing bacteria through the expression
of persister cells (Kåhström 2014) and also with the formation of spores which can
be hard to counter. Sporolation can complicate the treatment of chronic bacterial
infections as is the case with Clostridium difficile (Jarrad et al. 2015).
Bacterial persistence is defined as the development of antibiotic-tolerant slowgrowing persister cells as a sub-population within the bacterial population resulting
in difficulties with responses to antibiotic treatments and a biphasic killing curve
(Carvalho et al. 2019). Interestingly, another phenotypic response which seems to
be related to, but not the same as, persistence in some ways is that identified as the
Eagle Effect in which bacteria can have a higher level of survival when exposed
to antibacterial drug concentrations at higher levels than an optimal bactericidal
concentration. Under these conditions there is a net decrease in the rate of cell death
(Prasetyoputri et al. 2019).
An important and highly problematic further bacterial protective mechanism is
that of biofilm formation. This involves a multistep process and the ultimate protection of bacteria on surfaces by a covering layer which generally provides a shield from