ANTRUK’s Research Programmes

Developing a new antibiotic therapy by the early 2020’s

Antibiotic Research UK’s research programmes

Typically it can take up to 15 years and expenditure of many hundreds of millions of pounds to develop a new drug. ANTRUK aims to significantly reduce these timelines and costs by using smart approaches which will be very different to conventional drug development procedures. The Charity’s research focus initially will be on preserving our existing antibiotics rather than trying to find new ones.

  •  Multi-drug resistant (MDR) Gram-negative bacteria are the major risk to modern medicine.
  •  About 50% of all hospital infections are due to Gram-negative bacteria
  •  Of particular concern are antibiotic resistant bacteria associated with four different species, Klebsiella pneumoniaePseudomonas aeruginosa, Escherichia coli and Acinetobacter baumanii. All of these species can be found in the mouth, skin, blood, internal organs or gut
  •  A Multi Drug Resistant bacterium can be resistant in a host of different ways. For example the resistant bacteria can produce specific metallobeta-lactamases which are resistant to all penicillins and cephalosporins and all beta-lactamase inhibitors such as clavulanic acid and avibactam. These bacteria are also resistant to virtually all other antibiotics, with the exception of colistin
  • If resistance arises to colistin, which it has, then there are no treatments left.
 Diagram showing bacteria that are resistant to drugs Diagram courtesy of www.knowabouthealth.com showing the difference between non-resistant bacteria and drug resistant bacteria. Non-resistant bacteria multiply, and upon drug treatment, the bacteria die. Drug resistant bacteria multiply as well, but upon drug treatment, the bacteria continue to spread.

A number of authorities globally have spoken about the rapidly-emerging crisis of antibiotic resistance. There is an urgent need 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.

In particular the charity is focussing on repurposing or repositioning existing drugs.

This involves

  1. taking drugs that are currently used for one indication such as cancer treatment or heart disease and examining them for antibiotic activity
  2. combining two existing antibiotics to see if they can overcome antibiotic resistance or
  3. combining one or more drugs together with the antibiotic to see if the antibiotic resistance can be overcome (Antibiotic Resistance Breakers).

A picture showing how antibiotic resistance breakers work

 The first of the Charity’s research programmes has focussed on seeking Antibiotic Resistance Breakers in pharmacopoeia and nutraceutical libraries and in pan-resistant Gram-negative bacteria against five widely used antibiotic classes viz. meropenem, ciprofloxacin, aztreonam, gentamicin, colistin and tigecycline to which resistance in these bacteria has developed. Resistance can occur in a number of ways. One of these involves the loss of pores in the bacterial cell wall so that the antibiotic cannot penetrate the bacteria. If new pores could be created by the ARB then resistance might be overcome (see football analogy diagram)

 The Programmes

Research programmes and costs

 Test tube screening studies have been undertaken with pan-resistant Gram-negative antibiotic resistant bacteria. As these bacteria are hazardous, handling them requires specialist laboratory facilities in the United Kingdom that can handle these antibiotic resistant bacteria.
 Sites of action of gram-negative bacteria

This research programme was undertaken at both Evotec AG and LGC Ltd and was overseen by Dr Lloyd Czaplewski as project manager under the overall control of the Science Committee. Over 1500 different molecules were screened including antibiotic / antibiotic combinations. Arising from this screen a number of double antibiotic combinations were identified but these are unlikely to be clinically useful. Around 100 of the drugs that were initially screened, were subsequently screened at higher concentrations (> 40 micromolar) and some 5-6 hits were identified. As of the beginning of January 2018, more exhaustive screening studies are being undertaken.

 This project is focussing on taking some of the molecules identified in Research Project 1 and more exhaustively screening against a panel of clinical isolated. Resistance to the five antibiotic classes is being screened against in the Gram-negative bacteria Escherichia coli, Klebsiella pneumoniaePseudomonas aeroginosa and Acinetobacter baumanni. These test tube studies are taking the resistant bacteria and expose them to the five antibiotic classes.

This research programme is being overseen by Dr Lloyd Czaplewski as project manager under the overall control of the Science Committee.

 This project is focussing on clinically testing a non-antibiotic triple therapy for the treatment of travellers’ diarrhoea (TD) a common occurrence when UK residents visit parts of the world such as India and South East Asia as well as South America. Devised by Dr David Brown, previously a Trustee and chair of the Science Committee, as a result of literature mining, the triple therapy consists of one over the counter pharmaceutical drug and two nutraceuticals obtained from health food shops, The triple therapy is given orally and in a few case studies has been proven to be effective in treating TD sometimes within 30 minutes. In order to speed up recruitment and keep the costs low, the trial known as DIAMOND (DIarrhea Antibiotic Management using Over-the-counter Nutraceuticals in Daily practice) is being undertaken in

Jiangsu Province, China. The collaborators are Dr Jessika Hu (University of Hong Kong), Professor Paul Little, Dr Merlin Wilcox and Professor Michael Moore (University of Southampton), Dr David Brown (Alchemy Biomedical Consulting) and ANTRUK. As of January 2018, Ethics Committee approval has been obtained and recruitment is scheduled to commence in Q1 / Q2 2018 with the final results available by the end of 2018. Funding is being provided by ANTRUK jointly with Dr David Brown.

 

This project will focus on finding a new antibiotic from a chemical compound library, natural products or any other source. Gram-negative bacteria will be the target species and the library will either be obtained from commercial sources, provided by a pharmaceutical company, university or any other source of interesting compounds.

As this programme will examine novel compounds not hitherto used as drugs for any therapeutic area, by its nature it will be more expensive and take a longer time to complete than Projects 1-3.

This project will focus on finding a new antibiotic from a chemical compound library, natural products or any other source.. The focus of this project will be different from Project 4, either by examining a different library or using alternative screening systems and / or endpoints. Gram-negative bacteria will be the target species and the library will either be obtained from commercial sources, provided by a pharmaceutical company, university or any other source of interesting compounds.

As this programme will examine novel compounds not hitherto used as drugs for any therapeutic area, by its nature it will be more expensive and take a longer time to complete than Projects 1-3.