Tackling the resistance crisis

Discussing the potential “doomsday scenario” of a world without antibiotics, Professor Colin Garner, chief executive of Antibiotic Research UK (ANTRUK), says “not all is…bleak” as efforts are being made to remedy the situation

The serendipitous discovery by Sir Alexander Fleming in 1928 that mould which had accidentally contaminated a bacterial plate of Staphylococcus caused the bacteria to be killed led to a new world of infectious agent treatment. As Fleming himself later said: "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer, but I suppose that was exactly what I did." Who knows what might have happened if this accidental discovery had not been made.

Fleming, together with Florey and Chain, received the Nobel Prize for Medicine in 1945 in recognition of their work in discovering penicillin, characterising it chemically and developing manufacturing processes. In Fleming’s Nobel acceptance lecture, he said: “There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.

“The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” It is remarkable that the world has taken little notice of Fleming’s warnings issued 70 years ago!

Since the discovery of penicillin, some 200 further antibiotics have been discovered and marketed. The golden age of antibiotic development however is behind us. No new antibiotics with a novel mechanism of action have been found in the last 20 or 30 years. The antibiotic void has been compounded by many of the big pharmaceutical companies closing down their bacterial anti-infective programmes citing the lack of return on investment.

The lack of new antibiotics however is not solely down to a lack of investment. Billions of pounds have been spent by pharma on attempting to discover new antibiotics without success. Bacteria are very smart at adapting to antibiotic exposure and will inevitably develop resistance mechanisms. Resistance frequency to penicillin for example is as high a 1 per 10⁸. Also, most antibiotics will work only on growing bacteria and yet in any infection there is a sub-group of bacteria called persisters, which are resistant to antibiotics’ killing effects. Undoubtedly there is still a huge knowledge gap of bacterial metabolic pathways and how these can be up- or down-regulated to lead to bacterial cell death.

It is estimated that 700,000 people die each year from antibiotic resistant infections. There is a direct correlation between antibiotic misuse and antibiotic resistant morbidity or mortality. In Europe, 25,000 people die each year from antibiotic resistant infections, with a similar number in the US. It was reported recently that in any one year, five out of six Americans are prescribed a course of antibiotics, roughly double the frequency of the Swedes.

The problem of antibiotic resistance has now started to permeate the highest levels of Government. The WHO, the US President, the UK Prime Minister and the European Union have all highlighted the problem. David Cameron has asked well-known economist Jim O’Neill to chair The Antimicrobial Review Commission and come up with recommendations by 2016 of how the antibiotic discovery gap might be tackled. As of June 2015, O’Neill’s Commission have published three interim reports exploring different aspects of the antibiotic resistance problem. Some of the statistics they have come up with are truly frightening. Terms such as Doomsday scenario, pre-antibiotic era, death of medicine as currently practiced are just some of the terms being used to describe the current situation.

However, not all is as bleak as the situation described. Many small pharma and biotech companies are actively researching to find new antibiotics. The US FDA approved four new systemic antibiotics in 2015, the highest number in the last 10 years. One of these drugs, Zerbaxa (ceftolozane and tazobactam), is a cephalosporin together with a β-lactamase inhibitor for the treatment of systemic Gram-ve bacterial infections.

This is where ANTRUK comes into the picture. ANTRUK was formed in 2014 by an expert group of scientists and clinicians, all with a research interest in antibiotic resistance and all frustrated at the low profile and lack of funding for antibiotic resistance research in academia and the pharmaceutical sector.

The Charity’s goal is to bring one new antibiotic therapy to market by 2020, with subsequent introductions in the following decades. To achieve this, the Charity needs to raise up to £30 million over the next five years. In the context of drug development, this is a very small sum — typical drug development costs are in the £100s millions and take 10–15 years. ANTRUK hopes to achieve its goal by finding antibiotic resistance breakers (ARBs) from existing therapies drawn from any drug currently used to treat any disease. It is estimated that there are between 1,000–4,000 drugs in the pharmacopoeia library and all these will need to be screened.

Gram-ve bacteria are the Charity’s target since 1) these account for around 50% of hospital acquired infections 2) owing to their cell wall, these bacteria are the most intractable to antibiotic treatment and 3) antibiotic resistance in Gram-ve is increasing at an alarming rate. One attraction of a not-for-profit such as ANTRUK is that it can carry out research that may not be undertaken by the pharma sector since it is not essential to make a return on investment nor is it necessary to patent any discoveries. In addition, as ARBs will be found from currently marketed drugs, pre-clinical and clinical safety testing should be much reduced as for some of these drugs there will have been millions of patients exposed to therapeutic doses over many years.

To meet ANTRUK’s goals, we require funds. The Charity is currently conducting a fund-raising drive to raise £100,000 to start its scientific programmes. Anyone who wishes to assist us can donate through our website www.antibioticresearch.org.uk. We need your help to raise the profile of antibiotic resistance and to ensure our children and grandchildren can have the same medical treatments that we enjoy today.