PHARMACEUTICALS
NEW CLASSES OF ANTIBIOTICS IN DEVELOPMENT AGAINST WHO PRIORITY PATHOGENS Drug name Clinical
Bacterial target
development phase
Lefamulin Phase 3
Low MICs against pneumococci and
staphylococci, higher MICs against H. influenzae
Murepavidin (POL-7080)
Phase 2 Gepotidacin Phase 2 P. aeruginosa
Gram-positive and Gram- negative cocci – studied for treatment of gonorrhoea
Zoliflodacin Phase 2 gonorrhoea
Novel membrane targeting antibiotic
Novel bacterial topoisomerase II inhibitor (Triazaa- cenaphthylene)
Novel bacterial topoisomerase II inhibitor (Spiropyri- midenetrione)
Brilacidin Phase 2 S. aureus
Novel membrane targeting antibiotic
Afabicin (Debio-1450)
Phase 2 S. aureus
Zinplava (bezlotoxumab) was approved in 2017 to treat C. difficile infections. California-based Aridis Pharmaceuticals believes it will have the next two Mabs on the market in the next three to four years – Aerucin (AR-105), which is in Phase 2 trials to treat acute pneumonia caused by Gram-negative Pseudomonas aeruginosa, and Salvecin (AR- 301), which is in Phase 3 trials as an adjunct therapy for severe pneumonia caused by Staphylococcus aureus. ‘Monoclonal antibodies will address the resistance crisis because they work so differently to small molecule antibiotics,’ says Aridis CEO, Vu Truong. Unlike conventional antibiotics,
Mabs work by binding to the outside of specifically targeted bacteria. Their mode of action is either to neutralise the symptom-causing toxins produced by the bacteria, eg Salvecin targets the alpha-toxin released by S. aureus, or to improve immune recognition and destruction, eg Aerucin promotes phagocytic killing of P. aeruginosa. ‘There are some infections where people are asymptomatic,’ Truong says. ‘It makes sense to find these sub-populations to identify the antibodies. This is an exciting way to address antimicrobial resistance.’ Activity at the preclinical
FabI inhibitor
level also includes research into antibiotic resistance breakers to extend the effectiveness of traditional antibiotics, and super boosting conventional antibiotics by adding silver ions and other chemicals. At the University of Tubingen in Germany, a new class of antibiotics has been discovered after researching the chemicals bacteria use against each other when colonising the human nose. While most new antibiotics have been discovered in soil bacteria, the researchers postulated that harmless co-evolving and co-existing bacteria on the human body might have developed mechanisms to compete against aggressive pathogens, says University of Tubingen bacteriologist, Bernhard Krismer. The researchers discovered that
one bacterium found in the nasal cavity, Staphylococcus lugdunensis, produces a compound called lugdunin, which efficiently kills its close relative S. aureus. ‘We could clearly correlate the presence of this bacterium with the absence of S. aureus,’ Krismer says. While the team has not yet elucidated the mode of action of lugdunin, Krismer believes the compound is a promising new lead – despite its low solubility, which will be a hurdle for further development.
Pleuromutilind
Inhibits bacterial protein synthesis by binding at two sites to the peptidyltransferase centre of the ribosomal 50S subunit of the bacterial ribosome
Inhibits the lipopolysaccharide- assembly protein
New chemical structure that inhibits bacterial DNA replication
Inhibits bacterial DNA replication – different structure to Gepotidacin
Non-peptidic, fully synthetic mimic of Host Defense Proteins (HDPs), specifically defensin, targeting the IL-17 pathway
Targets the enzyme in the bacterial fatty acid biosynthesis pathway
Table 1 Source: Antibacterial Agents in Clinical Devel- opment: An Analysis of the Antibacterial Clinical Development Pipeline, Including Tuberculosis, World Health Organiza- tion 2017; http://apps.
who.int/iris/bitstream /10665/258965/1/ WHO-EMP-IAU-2017.11- engpdf?ua=1
Nabriva Drug class Mode of action Company
Polyphor GlaxoSmithKline
Entasis
Innovation Pharmaceuticals Debiopharm As with all new drugs, however,
Of 33 antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes
The solution to the anti- biotic resistance crisis also lies in infection prevention, reducing antibiotic use by humans and in agriculture, increased awareness, educa- tion and training, and improved surveillance to reduce the spread of resistance
funding remains a big problem. WHO estimates that it will cost billions to develop a new suite of antibiotics and alternative treatments. ‘Further investment from governments, civil society and industry is needed in R&D’ for new treatments, vaccines and diagnostics, says Zoubiane, adding that long-term incentives are needed for companies to develop the new antibiotics and therapies for the future. However, the solution to the antibiotic resistance crisis is not just about developing new antibiotics. Infection prevention is also important, Sprenger says, as is reducing the use of antibiotics by humans and in agriculture, increasing awareness and education, and training healthcare professionals to ensure better treatment decisions. There also needs to be better surveillance to reduce the spread of resistance, says Zoubiane. Even new drugs, meanwhile, will
continue to develop resistance. ‘We need to find a strategy not to overcome resistance, but to be able to live with and manage it,’ Brown reflects. ‘I’m more optimistic than some. It’s important to remember that before antibiotics were discovered, the human race didn’t die out.’
02 | 2018 21
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