ANTRUK’s Research Programmes

TARGET PRODUCT PROFILE (TPP)

Statement of medical need

A number of authorities globally have spoken about the rapidly-emerging crisis of bacteria becoming resistant to our best antibiotics. It has been described as threatening ‘the end of modern medicine.’

Multi-Drug Resistant (MDR) Gram-negative bacteria are a particular concern as we have few treatment options left for this class of bacteria. About 50% of all hospital infections are due to Gram-negative bacteria.

Antibiotic Research UK is focusing on four key Gram-negative bacteria, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii. All four species are common healthcare-associated pathogens, with E. coli also a common community pathogen. They epitomise the global concerns with antimicrobial resistance because resistance to multiple drug classes is encountered in each species, including to carbapenems, our most powerful antibiotic class. Carbapenem resistance is increasingly associated with production of carbapenemase enzymes, which resist licensed beta-lactamase inhibitors (e.g. clavulanate and tazobactam); some are even unaffected by novel inhibitors such as avibactam. These bacteria are also resistant to virtually all antibiotics, with the exception of colistin, an old (somewhat toxic) polymyxin class antibiotic, though colistin resistance has now emerged in many countries. There are no new classes of antibiotic on the horizon that will solve this problem entirely; some novel compounds are not active against all of the four species, others cannot overcome all of the resistance mechanisms.

Effect of antibiotic resistance on patients

Pathogens carrying these resistant carbapenemases (known as Carbapenem Resistant Enterbacteriaceae, CRE) cause many types of infections in the urinary tract, lungs, blood, and other organs. Patients with serious CRE infections have high mortality. If resistance arises to colistin, which it will, then there will be no treatments left. If this happens, which seems likely, then we will be unable to treat or prevent these infections. Childbirth will become hazardous for both mother and child. Adults in large numbers will present with untreatable community-acquired infections. Organ transplants and bone marrow transplants will be impossible. Major surgery for cancers, and immunosuppression for cancer therapy will also be virtually impossible. Mechanical devices such as metal hips and pacemakers will become associated with a much higher mortality because of infection by these MDR Gram-negatives. Without effective antibiotics, large swathes of modern medicine will not be feasible.

Patient ill in hospital fighting antibiotic resitant infection

 Our focus

There is an urgent need to to invent new antibiotics, though it may already be too late for this to happen in time and at the scale required. Therefore it is essential that we protect current antibiotics – particularly ‘last line of defence’ drugs – from resistance, and develop ‘Antibiotic Resistance Breakers’ (ARBs) that break the resistance that is sure to emerge.

Antibiotic Research UK is focused on developing three ARBs as initial priority, followed later by two new classes of antibiotic. The ARBs can be rapidly developed to fill the gap in the 2020s before new classes of antibiotic are discovered for clinical use in the 2030s.


Rationale for our approach

What is causing emergence of antibiotic resistance?

No new class of antibiotic for use against Gram-negative bacteria has been discovered for over 40 years. Yet resistance can begin to appear soon after introduction of a new antibiotic. The result is that European data indicate growing resistance to our major Gram-negative antibiotic classes such as carbapenems, cephalosporins, fluoroquinolones and aminoglycosides, and a 30% mortality rate for patients with septicaemia due to MDR E. coli. Data from the USA show a similar pattern. Asia, India and China have even higher rates of resistance to these classes, with levels reported in the range 50–80%. This has caused increased use of carbapenems which were earlier reserved for extreme cases in the very sick, immuno-compromised or as a last resort. This increased use is selecting for carbapenem-resistant Enterobacteriaceae (CREs; especially K. pneumoniae and E. coli) and other carbapenem-resistant organisms (including P. aeruginosa and A. baumannii), many of which produce carbapenemases. The most widely reported carbapenemases are KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi Metallo-beta-lactamase), VIM (Verona Integron-Mediated Metallo-beta-lactamase) OXA-type and IMP enzymes.They are encoded by genes transferable between bacteria, which greatly facilitates spread. CREs have been labeled “one of the three greatest threats to human health” by the World Health Organization and others.

Current known resistance mechanisms for our major classes of antibiotic

  •  carbapenems: resistance mediated by diverse drug-destroying carbapenemases, reduced cell permeability or up-regulated efflux of antibiotic;
  •  cephalosporins: resistance mediated by diverse ESBLs (Extended Spectrum Beta-Lactamases), AmpC beta-lactamases, or reduced permeability of antibiotic;
  •  fluoroquinolones: resistance mediated by mutational and plasmid-mediated mechanisms;
  •  aminoglycosides: resistance mediated by 16S rRNA methyltransferases,

Our goal is to develop broad-spectrum Antibiotic Resistance Breakers (ARBs) that overcome many of these mechanisms of resistance

Antibiotic Research UK is focused initially on developing ARB candidate drugs that are able to overcome the diverse mechanisms of resistance that have appeared to our major antibiotic classes. By selecting ARBs from current approved non-antibiotic drugs, clinical development can be much more rapid and lower risk than use of totally new molecules.

The validity of the antibiotic resistance breaker concept has been long proven with beta-lactamase inhibitor combinations, such as co-amoxiclav (amoxycillin plus clavulanic acid) and piperacillin-tazobactam; as testament to this successful strategy, several others are being developed currently. However, beta-lactamase inhibition alone may not solve the MDR Gram-negative problem. Broad-spectrum ARBs are required that can protect antibiotics classes other than beta-lactams. One ARB may be able to resuscitate several different classes of antibiotic, but not all of them. So more than one ARB will likely be required. We intend to bring three into clinical use during the 2020s.

tablets

 Target Product Profiles for 3 Antibiotic Resistance Breakers

General criteria for selection of an Antibiotic Resistance Breaker (ARB):

Each of the three products is a molecule to be co-administered with an antibiotic, to break resistance. Molecules will be selected from currently approved and available (non-antibiotic) drugs, nutraceuticals or pure active ingredients of foodstuffs acknowledged as satisfying internationally-agreed GRAS (Generally Regarded as Safe) standards, to allow rapid, safe and low-risk development.

Molecules will be selected that, in the laboratory, have different profiles of effects in breaking resistance: we aim to select a different one for three of the major antibiotic classes used against Gram-negative bacteria.

Preclinical criteria

Three different ARBs will be selected based on the following criteria:

  •  from different chemical classes.
  •  break resistance to at least one antibiotic class mediated by one or more genetic mechanisms in several or all of the four targeted MDR Gram-negative bacterial species.
  •  low propensity for rapid emergence of bacterial resistance.
  •  intravenous dosing in humans is possible (potency, solubility, safety, excretion)
  •  concentrations required for ARB activity are no higher than the plasma range achieved by the molecule in current use.
  •  co-administration in vivo of the ARB with the partner antibiotic is possible:
    • co-formulation with the partner antibiotic is achievable.
    • pharmacokinetic properties of the combination are acceptable.
    • safety of the combination is acceptable.
  •  Low cost of goods, affordable globally.

Clinical criteria

Indication:
  • Primary indication: combination therapy for treatment of life-threatening infection by Gram-negative bacteria requiring hospitalisation.
  • Secondary indication: potential to be developed for oral therapy.
Route of administration:
  • Primary: intravenous, for use in hospitals.
  • Secondary: oral, for hospital and GP use.
Dose form:
  • Fixed dose combination.
  • Primary: single formulation for intravenous dosing. Available as a pre-formulated solution or as dry powder to be rehydrated.
  • Secondary: single tablet for oral administration, total dose under 1 gram.
  • Intravenous form storage minimum stability 6 months. Oral dose form storage minimum 2 years.
  • Heat stable.
Dose frequency:
  • Primary: intravenous, QD.
  • Secondary: oral, 1-3 times daily.
Efficacy:

Antibiotic resistance is reduced or eliminated allowing renewed use of antibiotic at approved therapeutic dose level and dosing schedule.

Safety:
  • No safety issues added incremental to those of the original antibiotic.
  • Suitable for use in all age groups, infant, child, adult.
  • No abuse potential.