1.1 Bacteria
3
Tackling the antibacterial resistance problem presents key multi-disciplinary
research challenges across the fundamental, preclinical and clinical sciences. The
development of new antibacterials to treat Gram-negative pathogen-mediated disease
is particularly critical, as there is only a relatively small number of drugs approved or
in the pipeline which could potentially treat infections resulting from multidrug resistant Gram-negative ESKAPE bacterial pathogens. The ESKAPE pathogens include
Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp., the last four of
which are Gram-negative. This weakness in the armoury against human pathogenic
Gram-negatives has been noted in the excellent clinical antibiotic pipeline update
in the review by Butler et al. (2017) as well as in another review by Koulenti et al.
(2019), focussing on new drugs and potential future ones active against multidrugresistant Gram-negative bacteria (Koulenti et al. 2019). Further helpful detail is also
provided in the article by Breijyeh et al. (2020) including approaches to try and
resolve the issue with resistant Gram-negatives. The seriousness of this situation
cannot be overemphasized especially as in some cases virtually no effective antibacterials are available. While the issue needs to be assessed at a global level, therapeutic
efficacy differences also appear at country, community and individual levels, the last
as illustrated by a tragic fatal case of infection with cPan-drug resistant Klebsiella
pneumoniae: an isolate of this bacterium was resistant to 26 antibiotics (Chen et al.
2017).
Although neither Gram-negative nor Gram-positive, extremely drug resistant
(XDR) Mycobacterium tuberculosis is also a great health concern, and specifics on
antibacterial development possibilities for tuberculosis are covered in Mishra et al.
(2017) including clinical manifestations of the disease, existing therapies and drugs
in the pipeline, molecular targets for antimycobacterial agents, assay techniques,
and alkaloids with activity against this pernicious mycobacterium. A further detailed
coverage of all aspects of this major disease burden on global health, including recent
drug developments and drug trials, is given in the annual WHO reports (World Health
Organisation 2018, 2019a).
Antibacterial agents in the clinical development pipeline have been well analysed
by a number of groups including by Theuretzbacher and colleagues (Theuretzbacher
et al. 2019, 2020a), Butler and Paterson (2020), and the World Health Organisation
(2017a, 2019b). A useful report by The Pew Charitable Trusts (2016) highlighted the
pressing need to increase the number of new antibacterial drugs in the pipeline in a
holistic overview of the scientific priorities involved and ways to try and meet them.
These Trusts also provide regular updates in this area and as of December 2019 around
41 new antibiotics with the potential to treat serious infections caused by bacteria in
global clinical development (The Pew Charitable Trusts 2020). Agents in the preclinical phase have also been analysed by Theuretzbacher et al. (2020b) and the World
Health Organisation (2019c). While it is encouraging to have a number of compounds
in the preclinical pipeline there is still an urgent need for more, particularly from
different structural types and with new modes of action.
In view of the multi-dimensional nature of the bacterial disease challenge, various
treatments have been, and are being, pursued. These include preventative hygiene
3
Tackling the antibacterial resistance problem presents key multi-disciplinary
research challenges across the fundamental, preclinical and clinical sciences. The
development of new antibacterials to treat Gram-negative pathogen-mediated disease
is particularly critical, as there is only a relatively small number of drugs approved or
in the pipeline which could potentially treat infections resulting from multidrug resistant Gram-negative ESKAPE bacterial pathogens. The ESKAPE pathogens include
Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp., the last four of
which are Gram-negative. This weakness in the armoury against human pathogenic
Gram-negatives has been noted in the excellent clinical antibiotic pipeline update
in the review by Butler et al. (2017) as well as in another review by Koulenti et al.
(2019), focussing on new drugs and potential future ones active against multidrugresistant Gram-negative bacteria (Koulenti et al. 2019). Further helpful detail is also
provided in the article by Breijyeh et al. (2020) including approaches to try and
resolve the issue with resistant Gram-negatives. The seriousness of this situation
cannot be overemphasized especially as in some cases virtually no effective antibacterials are available. While the issue needs to be assessed at a global level, therapeutic
efficacy differences also appear at country, community and individual levels, the last
as illustrated by a tragic fatal case of infection with cPan-drug resistant Klebsiella
pneumoniae: an isolate of this bacterium was resistant to 26 antibiotics (Chen et al.
2017).
Although neither Gram-negative nor Gram-positive, extremely drug resistant
(XDR) Mycobacterium tuberculosis is also a great health concern, and specifics on
antibacterial development possibilities for tuberculosis are covered in Mishra et al.
(2017) including clinical manifestations of the disease, existing therapies and drugs
in the pipeline, molecular targets for antimycobacterial agents, assay techniques,
and alkaloids with activity against this pernicious mycobacterium. A further detailed
coverage of all aspects of this major disease burden on global health, including recent
drug developments and drug trials, is given in the annual WHO reports (World Health
Organisation 2018, 2019a).
Antibacterial agents in the clinical development pipeline have been well analysed
by a number of groups including by Theuretzbacher and colleagues (Theuretzbacher
et al. 2019, 2020a), Butler and Paterson (2020), and the World Health Organisation
(2017a, 2019b). A useful report by The Pew Charitable Trusts (2016) highlighted the
pressing need to increase the number of new antibacterial drugs in the pipeline in a
holistic overview of the scientific priorities involved and ways to try and meet them.
These Trusts also provide regular updates in this area and as of December 2019 around
41 new antibiotics with the potential to treat serious infections caused by bacteria in
global clinical development (The Pew Charitable Trusts 2020). Agents in the preclinical phase have also been analysed by Theuretzbacher et al. (2020b) and the World
Health Organisation (2019c). While it is encouraging to have a number of compounds
in the preclinical pipeline there is still an urgent need for more, particularly from
different structural types and with new modes of action.
In view of the multi-dimensional nature of the bacterial disease challenge, various
treatments have been, and are being, pursued. These include preventative hygiene