​“When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer. But I suppose that was exactly what I did." Sir Alexander Fleming.

The serendipitous discovery of penicillin in September 1928 by Scottish scientist Sir Alexander Fleming is often cited as one of the most famous accidental discoveries of all time. It wasn’t until the 1940s, however, that penicillin was introduced into the mass market by Howard Florey and Ernst Chain; a process that heralded the beginning of what would become known as the ‘modern era of antibiotics’.          

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                               Alexander Fleming in his laboratory at St Mary's, Paddington, London. Image Credit:                                                                          Photograph TR 1468  from the collections of the Imperial War Museums ​

Over the past 80 years, antibiotics of various classes have gone on to become some of the most successful drugs in medical history, saving millions of lives worldwide. Thanks to innovative medicine, illnesses that once killed, such as septicaemia and meningitis, have become controllable.  Through their inhibition of protein synthesis and cell wall biosynthesis, induced-DNA damage and much more, antibiotics have long secured their place as a weapon in the mighty arsenal of modern medicine.

However, the climate is changing, and the threat of antimicrobial resistance is looming.  In January 2017, news broke out that a woman in Nevada had been killed by a pan-resistant form of Klebsiella pneumoniae that was resistant to 26 different antibiotics. Sadly, this is not an isolated case. According to the Centers for Disease Control and Prevention, ‘at least 2 million people become infected with bacteria that are resistant to antibiotics per year in the United States and at least 23,000 people die as a result of these infections.’ The numbers of cases of multi-drug resistant bacteria is increasing at a startling rate. 

So what is antimicrobial resistance?

Antimicrobial resistance is the ability of a microorganism such as bacteria, viruses, and some parasites, to resist the effects of medication that has previously been used to treat them. It develops from an evolutionary response known as natural selection and can have deadly consequences for the host.  Microbes develop resistance due to exposure. In other words, within any one population of bacteria, some microorganisms will be naturally drug resistant due to some kind of mutation. When a patient is treated with antibiotics, all of the non-resistant bacteria will be killed, along with many of the good bacteria which form part of your natural microbiome, a collective name for all the microorganisms in a particular environment. In the absence of competition, the drug-resistant bacteria can grow exponentially and free from factors that would normally limit their growth.   

If that wasn't bad enough, some bacteria can give their drug-resistance genes to other bacteria of the same species (vertical transmission) or a different species (horizontal transmission). The result is the development of multi-drug resistant strains such as the hospital superbug, Methicillin-resistant Staphylococcus Aureus, more commonly known as MRSA. By overusing or misusing antibiotics, we are driving the evolution of this resistance. 

Why is it such a big deal?​

It’s a familiar scenario; when you are ill you visit your local GP who prescribes you a healthy dose of antibiotics and within a few days your symptoms are improving. Now imagine a world where that isn’t possible.  A time where antibiotics do not work as they used to, infections last longer, cause more severe illness and involve more expensive and harmful medications.  Alarmingly, if sufficient action is not taken, the idea that infectious diseases are non-curable due to high levels of multiple drug resistant pathogens may soon become reality.  

 Antibiotic resistance is arguably one of the greatest threats of the 21^st century. It can affect anyone, of any age, in any country. It can cross international boundaries with remarkable speed to the extent that some world health leaders have coined the term ‘nightmare bacteria’ to describe these troublesome antibiotic-resistant microorganisms. 

Not only are microbes quickly developing resistance to antibiotics but the rate of new antibiotic drug discovery is much slower than it used to be. Most drugs currently in the clinical pipeline are modifications of existing classes of antibiotics and are only short-term solutions.                    

In February 2017, the World Health Organisation published its first ever global priority pathogen list– a catalogue of 12 families of bacteria including Acinetobacter, Pseudomonas and various Enterobacteriaceae, characterised according to their perceived threat to human health and the urgency of need for new antibiotics.                          

If we consider how many lives have been saved and how significantly antibiotics have contributed to the control of infectious diseases, the idea that they may no longer work as efficiently as once intended is a sorry prospect indeed, a future without such reliance seems incredibly daunting.

Whilst public health agencies and governments hone in on global campaigns to raise awareness and understanding of antimicrobial resistance, scientists must strive to strengthen knowledge through research.  

 It is truly a race against the clock. 

Anti-microbial research at ISIS 

Here at ISIS, scientists from all over the world are using neutrons and muons to study the structure and dynamics of complex biological systems. In doing so, the foundations can be set for research into microorganisms and the development of new antibiotics.  

Over the past few years, ISIS has built a strong portfolio of biophysical research in the field of antimicrobial resistance. For example, in 2013, a collaboration of scientists from Queen Mary University London, ISIS, The University of Toronto, The University of Szeged and Beijing Normal University reported the first successful characterisation of a natural antibiotic using neutrons, 85 years after its chance discovery by Alexander Fleming. The antibiotic in question, penicillin, is one of the first and most widely used antibiotic agents that has saved millions of lives worldwide. Using the TOSCA instrument at ISIS, the research team used neutrons to uncover the complexity at the core of this natural wonder in the hope that it would facilitate the rational understanding and design of new antibiotics.                                              

More recently in 2015, researchers at the ISIS Neutron and Muon Source and Newcastle University created the first working model of the outer membrane of the bacterium Escherichia coli (E.coli). The synthetic model, constructed at ISIS and measuring 1/10,00^th the thickness of a sheet of A4 paper, will serve as a robust system and important tool in drug design, particularly for the development of antibiotics. Project leader Professor Jeremy Lakey from Newcastle University explained that the results were incredibly promising; “we have built, for the first time, a working bacterial membrane. Now we can find out how the membrane works and design drugs to cross it.”        

In the same year, researchers used X-ray and neutron reflectivity techniques to examine the role of calcium ions in the stability of a model Gram negative bacteria-outer membrane. Neutron reflectometry has also been used to study the role of the uncharged sugar groups in the outer core region of lipopolysaccharide (LPS) in protecting the phosphate-rich inner core region from electrostatic interactions with antimicrobial proteins.  

Speaking in 2017, Dr Luke Clifton explains how the research has progressed in the past couple of years;

“Here at ISIS, we are able to resolve molecular level details of the interaction of antibiotic compounds with the Gram negative bacterial outer surface. This is done using model biological systems composed of extracted bacterial components with the same arrangement as found in the microbe. This year we have focussed on increasing the accuracy and complexity of the model systems in addition to examining the interaction of clinical antibiotics with these bacterial surface models. The unique ability of neutron scattering techniques to resolve complex structures makes it a powerful probe for this research." 

Further examples of AMR experiments conducted at ISIS include a neutron reflectivity study conducted by scientists from Kings College London who used neutrons to gain insight into the effects of the antimicrobial peptides Rhesusθ-defensin 1 and porcine protegrin 1 on model bacterial cell membranes. Another group investigated the implications of lipid monolayer charge characteristics from mammalian and eukaryotic cells on their selective interactions with antimicrobial peptides (AMPs) which are small molecular weight, host defence proteins with broad spectrum antimicrobial activity, used as part of the innate immune response to infection. 

 The examples highlighted above represent only a small fraction of the cutting-edge antimicrobial research undertaken here at ISIS. Whilst scientists continue to strive to discover new- or improve existing – antibiotics, everyone can play their part in the battle against resistant microbes. By preventing the misuse of antibiotics in humans and animals, ensuring that correct advice is sought from health care professionals before taking antibiotics and maintaining good hygiene in order to prevent infection, we can collectively reduce the threat. In the words of the World Health Organisation campaign; “No action today. No cure tomorrow."  

For science highlights based on antimicrobial research at ISIS please visit this link

An introduction to neutron reflectivity can be found on our website.