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Antibiotics and antibiotic resistance Spotlight on Antibiotic Research UK
Colin Garner
Medicine as currently practised throughout the world is threatened by the rise of antibiotic resistant (Chief Executive, Antibiotic infections. In 2014 it was reported that 50,000 people a year die from antibiotic resistant infections in the USA and Europe. Worldwide there may be as many as 700,000 deaths a year. Jim O'Neill, the eminent economist and David Brown
appointed by the Prime Minister as chair of the Government Review of Antimicrobial resistance recently (Chair, Antibiotic Research stated "For doctors and for those who have experienced first-hand the anxiety of an infection that is drug- UK Science and Technical resistant, as a patient or when caring for a loved one, there is little need to prove the importance of tackling Advisory Committee) antimicrobial resistance."1,2 The Prime Minister stated in 2014 that the world could soon be "cast back into the dark ages of medicine" unless action is taken to tackle the growing threat of resistance to antibiotics"3.
Similar views have been expressed by The World Health Manchester, Newcastle, Nottingham, Oxford, Southampton, Organisation4, the President of the United States5, the UK St Georges London, Strathclyde, Warwick and York. While Chief Medical Officer6 and many others. Bacteria are fast these pharmaceutical companies and organisations are becoming resistant to antibiotics and there has been a dearth also involved in the network: Chemical Biology Ventures, of new antibiotics discovered during the past 30 years as the Euprotec, Evotech, Garner Consulting, John Innes figure shows. A major reason for the lack of new antibiotics Research Centre, Novacta Biosysystems, P A Consulting, stems from the closing down of antibiotic research Pharmabioquintet, Redex Pharma, Sealife Pharma, Selcia programmes by the large pharmaceutical companies who and Transcrip Partners. are unable to make a financial return on antibiotic drugs The Scientific and Technical Committee (STAC) has determined that the initial research programmes wil It is easy to forget what a world without antibiotics focus on Antibiotic Resistance Breakers (ARBs). ARBs are looks like. Ordinary surgery becomes more risky and molecules that when combined with an antibiotic overcome medical interventions ranging from surgeries requiring antibiotic resistance. ARB candidate drugs should be capable immunosuppression to simple wound treatments would of overcoming the diverse mechanisms of resistance that be compromised or even impossible without antibiotics. have appeared to our major antibiotic classes. We will select Mortality in childbirth and diseases such as meningitis three ARBs from current approved non-antibiotic drugs; as and pneumonia would increase dramatical y. The rise of a result clinical development can be much more rapid and antibiotic resistance could mean that we go back again to lower risk than use of total y new molecules. ARBs could be this ‘pre-antibiotic era'.
drawn from (a) existing therapeutics from all disease areas Concerned by the lack of progress in antibiotic (b) nutraceuticals and (c) new chemical entities. ARBs to be development a network of eminent UK scientists came screened will be targeted at four Gram-negative antibiotic together to discuss what could be done. Arising from these resistant bacteria – Pseudomonas aeruginosa, Acinetobacter discussions charity Antibiotic Research UK – developing baumannii, Escherichia coli and Klebsiella pneumonia. These new antibiotics (ANTRUK) was formed to fund novel four species account for a high percentage of all hospital approaches to antibiotic development. The charity's initial acquired infections7,8 and are the ones the Charity is most target is to raise £30m in the next 5–7 years with the aim of keen to tackle early on. The concept of ARBs is not novel; developing one new antibiotic therapy by 2020 with further a number of marketed drugs consist of an antibiotic plus drugs coming through in the following decade. another drug such as a β-lactamase inhibitor e.g. Clavulanic The Scientific and Technical Committee (STAC), acid or clavulanate, usual y combined with amoxicillin chaired by Dr David Brown, has identified research areas (Augmentin) or ticarcillin (Timentin), and Sulbactam, considered to yield the best potential for the most rapid usual y combined with ampicillin (Unasyn) or Cefoperazone development of new classes of antibiotic. (Sulperazon). A review on ARBs will shortly be published9. The research programmes will be undertaken by It is intended ultimately the whole pharmacopoeia library a network of leading scientists and clinicians in UK will be screened (1000 to 4000 drugs) before examining universities and specialty pharmaceuticals companies New Chemical Entities (NCEs). ■
within their existing laboratories and organisations. This network will bring together intellectual insights and ANTRUK is a national charity dedicated to finding new antibiotics development abilities of exceptional quality and at a lower against resistant bacteria. It aims to raise money primarily in the Figure 1. Dates for cost than hitherto available. Members of the network are UK and is seeking support from Foundations, Trusts, Industry
antibiotic discovery and drawn from the following universities: Aston, Birmingham,
and the general public. The Charity is a Charitable Incorporated the ‘discovery void' Bristol, Cambridge, Kings College London, Leeds, Organisation (CIO) and is able to act as a not for profit company. 36 June 2015 Biochemical Society

Antibiotics and antibiotic resistance Target Product Profile
Professor Colin Garner is Chief Executive of Antibiotic Research UK. He has ANTRUK has prepared a Target Product Profile (TPP) for the molecules to be first screened in vitro. spent a lifetime entrepreneurial career in academic and commercial science General criteria for selection of an Antibiotic Resistance Breaker (ARB)
principally in pharmacology, toxicology Each of the three products is a molecule to be co-administered with an antibiotic, to and cancer research. He is passionate break resistance. Molecules will be selected from currently approved and available (non- that the problem of antibiotic resistance must be addressed now antibiotic) drugs, nutraceuticals or pure active ingredients of foodstuffs acknowledged as and that the charity sector must play a key role. email: colin. 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 Dr David Brown is Chair of Antibiotic used against Gram-negative bacteria.
Research UK's Science and Technical Advisory Committee. His career has been Three different ARBs will be selected based on the following criteria: in pharmaceutical drug development • from different chemical classes working at senior research management • break resistance to at least one antibiotic class mediated by one or more genetic levels in companies such as Roche, Pfizer, mechanisms in several or all of the four targeted multidrug resistant Gram-negative Zeneca and GlaxoWellcome. He is committed to ensuring the charity bacterial species meets its goal of bringing one new therapy into the clinic by 2020. • 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 1. O'Neill, J., Antimicrobial Resistance: Tackling a crisis for the • co-administration in vivo of the ARB with the partner antibiotic is possible health and wealth of nations. The review on antimicrobial • 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 of%20nations_1.pdf, December 2014 2. O'Neill, J., Tackling a global health crisis: initial steps. Tackling a global health crisis: initial steps. The Review • Primary indication: combination therapy for treatment of life-threatening infection by on Antimicrobial Resistance. http://amr-review.org/sites/ Gram-negative bacteria requiring hospitalisation default/files/Report-52.15.pdf, February 2015 • Secondary indication: potential to be developed for oral therapy 3. Cameron, D., Prime Minister warns of global threat of Route of administration: • Primary: intravenous, for use in hospitals • Secondary: oral, for hospital and GP use resistance, July 2014 4. Organization, W.H., The evolving threat of antimicrobial • Fixed dose combination resistance. Options for action. http://whqlibdoc.who.int/ • Primary: single formulation for intravenous dosing • Available as a pre-formulated solution or as dry powder to be rehydrated 5. Technology, P.s.C.o.A.o.S.a., Report To The President On • Secondary: single tablet for oral administration, total dose under 1 gram • Intravenous form storage minimum stability 6 months. Oral dose form storage minimum sept_2014_final.pdf, September 2014 6. Davies, S., Annual Report of the Chief Medical Officer. • Primary: intravenous, QD • Secondary: oral, 1-3 times daily Volume_2_2011.pdf, 2011 7. Peleg, A.Y. and D.C. Hooper (2010) N. Eng. J. Med. 362,
• Antibiotic resistance is reduced or eliminated allowing renewed use of antibiotic at approved therapeutic dose level and dosing schedule.
8. Farrell D.J., Flamm R.K. and Jones R.N. (2009–2011) (2014) Diagn. Microbiol. Infect. Dis. 78, 443-448
• No safety issues added incremental to those of the original antibiotic.
9. Brown, D. (2015) Antibiotic Resistance Breakers: Can • Suitable for use in all age groups, infant, child, adult.
repurposed drugs fill the antibiotic discovery void? Nat. Rev. • No abuse potential.
Drug Discov. In press June 2015 Biochemical Society 37

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