180
5 Future Possibilities
Bacterial antigens
Circulating bacterial antigens (Nuti et al. 2011) also afford possible targets for therapies involving minimalised antibodies as pharmaceuticals (Rader 2015). Further
studies in this area cover the use of synthetic immunotherapeutics against Gramnegative pathogens (Feigman et al. 2018). The design idea in this work was to
use a conjugate based on polymixin B as the bacterium surface targeting agent
and an antigenic epitope that can recruit antibodies found in human serum, with
ultimate bacterial cell destruction. With an appropriate lipid side chain the conjugate itself can also be antibacterial against Gram-negative bacterial pathogens. So
basically a two-pronged activity approach is used but extension to a three-pronged
attack might increase potency even further while selectively targeting the problematic
Gram-negatives.
5.7 Concluding Remarks
While various non-small molecule approaches to control bacterial pathogens are
on-going including lysins, probiotics, phages, immune stimulation and vaccines, the
emphasis in this book has been on the small molecule multi-targeting/activity design
side. However, although current approaches to multi-activity have been productive,
there is an urgent need to broaden the scope by thinking outside the square, including
‘outside the bug’ (Monserrat-Martinez et al. 2019), and considering the forest as well
as the trees.
This raises a more fundamental question in just how does one think outside the
square? How do you know you are outside? Or how does one ‘imagine the unimaginable’ as noted by Professor Ben Feringa at the end of his Nobel Prize Lecture
(Feringa 2017). Is it all just serendipitous or can the likelihood of serendipitous
discoveries be assisted by the nature of the journey, the paths one is on, or is something totally different required? Perhaps some pointers to answers can be taken from
neural network representations and the formalisms or algorithms involved in neural
network based artificial intelligence.
Also it is suggested that other answers are likely to come from looking carefully
to nature again with new eyes and questions. Perhaps questions along the lines of:
How is antibiotic resistance controlled in nature of which we are an integral part?
Why is resistance not induced by antibiotics in their natural settings or is it? How do
soil bacteria or microbiome bacteria (or other bacteria in competitive environments)
overcome resistance to their secreted antibiotics to control other competing bacteria?
Possibly there is a hint here based on recent work on a novel alkaliphilic Streptomyces
species (sp. myrophorea, isolate McG1) from a Northern Ireland soil sample with
activity against ESKAPE pathogens. The Streptomyces strain was resistant to 28 out
of 36 clinical antibiotics and from in silico based gene analysis had many secondary
metabolite and toxicity resistance gene clusters as well as a number of antibiotic resistance genes possibly related to antibiotic production (Terra et al. 2018). Interestingly,
5 Future Possibilities
Bacterial antigens
Circulating bacterial antigens (Nuti et al. 2011) also afford possible targets for therapies involving minimalised antibodies as pharmaceuticals (Rader 2015). Further
studies in this area cover the use of synthetic immunotherapeutics against Gramnegative pathogens (Feigman et al. 2018). The design idea in this work was to
use a conjugate based on polymixin B as the bacterium surface targeting agent
and an antigenic epitope that can recruit antibodies found in human serum, with
ultimate bacterial cell destruction. With an appropriate lipid side chain the conjugate itself can also be antibacterial against Gram-negative bacterial pathogens. So
basically a two-pronged activity approach is used but extension to a three-pronged
attack might increase potency even further while selectively targeting the problematic
Gram-negatives.
5.7 Concluding Remarks
While various non-small molecule approaches to control bacterial pathogens are
on-going including lysins, probiotics, phages, immune stimulation and vaccines, the
emphasis in this book has been on the small molecule multi-targeting/activity design
side. However, although current approaches to multi-activity have been productive,
there is an urgent need to broaden the scope by thinking outside the square, including
‘outside the bug’ (Monserrat-Martinez et al. 2019), and considering the forest as well
as the trees.
This raises a more fundamental question in just how does one think outside the
square? How do you know you are outside? Or how does one ‘imagine the unimaginable’ as noted by Professor Ben Feringa at the end of his Nobel Prize Lecture
(Feringa 2017). Is it all just serendipitous or can the likelihood of serendipitous
discoveries be assisted by the nature of the journey, the paths one is on, or is something totally different required? Perhaps some pointers to answers can be taken from
neural network representations and the formalisms or algorithms involved in neural
network based artificial intelligence.
Also it is suggested that other answers are likely to come from looking carefully
to nature again with new eyes and questions. Perhaps questions along the lines of:
How is antibiotic resistance controlled in nature of which we are an integral part?
Why is resistance not induced by antibiotics in their natural settings or is it? How do
soil bacteria or microbiome bacteria (or other bacteria in competitive environments)
overcome resistance to their secreted antibiotics to control other competing bacteria?
Possibly there is a hint here based on recent work on a novel alkaliphilic Streptomyces
species (sp. myrophorea, isolate McG1) from a Northern Ireland soil sample with
activity against ESKAPE pathogens. The Streptomyces strain was resistant to 28 out
of 36 clinical antibiotics and from in silico based gene analysis had many secondary
metabolite and toxicity resistance gene clusters as well as a number of antibiotic resistance genes possibly related to antibiotic production (Terra et al. 2018). Interestingly,