PHARMACEUTICALS
with any of the antibiotics currently on the market,’ WHO says. Despite the increased
commitment to R&D, however, a WHO report in September 2017 lamented the ‘serious lack of new antibiotics under development’. As of May 2017, the report records a total of 51 antibiotics (including drug combinations) and 11 biologicals in the clinical pipeline, with 42 new therapeutic entities – 33 antibiotics and nine biologicals – targeting the ‘priority pathogens’ identified by WHO, as well as seven for tuberculosis and nine for C. difficile infections. However, most of the drugs in the pipeline are modifications of existing classes of antibiotics and ‘are only short-term solutions’.
Among the 33 new chemical entity antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes. There are 16 products, both antibiotics and biologics, with activity against one or more Gram-positive priority pathogens – although mostly targeting methicillin-resistant Staphylococcus aureus (MRSA) – including two new antibiotic classes. Meanwhile, ‘the situation is worse for Gram-negative bacterial infections’, says WHO. Of 10 products in Phase 1 trials, ‘almost all the agents are modifications of existing antibiotic classes … active only against specific pathogens or a limited subset of resistant strains’. WHO also highlights tuberculosis as ‘neglected’, with only seven new agents for TB currently in clinical trials. Around 10 new antimicrobial
drug approvals are expected over the next five years. ‘However, these potential new treatments will add little to the already existing arsenal and will not be sufficient to tackle the impending AMR threat,’ WHO warns. ‘More investment is needed in basic science, drug discovery and clinical development, especially for the critical priority Gram-negative carbapenem-resistant pathogens P. aeruginosa, A. baumannii and Enterobacteriaceae.’ Marc Sprenger, director of WHO’s
antimicrobial resistance secretariat, is ‘not that optimistic’ about the current clinical pipeline. ‘There has been no big breakthrough. The pipeline is not well filled and the prospect of success is not good even
It’s not just the fact that resistance is increasing – that’s inevitable. The issue is more the rate of increase in resistance, which appears to be accelerating
Nick Brown director, Antibiotic Action > 50%
of Escherichia coli isolates sampled across Europe are resistant to at least one antibiotic, with resistance rates increasing between 2013 and 2016
Apart from the approval of linezolid in 2000, no new classes of antibiot- ics have been approved since the early 1980s, with the last new class to treat gram-negative bacteria discovered in 1962
though there is action to accelerate this area. But it’s very difficult to develop new antibiotics and there are financial issues,’ he says. ‘I can only hope we find new classes of drugs, but how do we make sure they are only used when there is no other alternative? Say we find a new antibiotic, within a couple of years there will be resistance. It’s very difficult.’ Marie Petit, co-ordinator of the BEAM Alliance, a network of small and medium-sized European biopharmaceutical companies tackling antibiotic resistance, is of a similar mindset. ‘There has been little progress in R&D over the past decades. While small and medium sized enterprises (SMEs) hold most of the innovative pipeline, this is too small and difficult to develop as the R&D ecosystem remains very much underserved,’ she says. ‘Innovation is mainly incremental. To make concrete progress we need
WHO PRIORITY PATHOGENS LIST
Priority 1: CRITICAL Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant, ESBL (extended spectrum beta lactamase)-producing
Priority 2: HIGH Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin- intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter spp., fluoroquinolone-resistant Salmonellae, fluoroquinolone-resistant Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
Priority 3: MEDIUM Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant
a large toolbox of new drugs, both broad and narrow spectrum, but also non-antibiotic approaches to decontaminate, prevent, switch off resistance mechanisms, limit side effects, as well as rapid and accurate diagnostics and surveillance data. This way we would be armed to move forward.’
BEAM members, Petit says, are
involved in 25 clinical projects. UK- based Destiny Pharma, for example, has developed the antibacterial drug XF-73 (exeporfinium chloride), a synthetic dicationic porphyrin derivative in Phase 2 clinical trials against Staphylococcus aureus infections including MRSA. The drug is expected to hit the market within the next four years. ‘Destiny has spent about 15 years tackling antibiotic resistance. Our drug won’t solve all the issues but it will be a significant breakthrough,’ says Bill Love, Destiny’s founder and chief scientific officer, who was recently appointed to the UK government’s Global Anti-Microbial Resistance Innovation Fund. The drug works by targeting the outside of the bacterial membrane, by making the bugs ‘selectively permeable’ or leaky. Love says the drug acts within 15 minutes, although he notes it is less effective against Gram-negative bacteria. The researchers believe the drug interacts with the bacterial membrane by electrostatic interaction, changing its charge and causing it to exude some of its intracellular contents. ‘It’s a subtle but deadly interaction,’ Love says. ‘We haven’t pinned down the precise mode of action, but no other agent we’re aware of acts against the bacterial membrane as the XF drugs do. The membrane is an unexploited target.’ The researchers were unable to
detect any signs of drug resistance even after 55 days of repeat exposure. Love suggests this is because of the speed it kills, giving the bacteria less time to develop resistance. As a consequence, Love believes the drug should have a long clinical life as a preventative therapy, and says it could also preserve and extend the lifetime of existing antibiotics. Another area of growing interest
for their anti-infective properties, meanwhile, are monoclonal antibodies (Mabs). Merck’s
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