The problem, and the crisis

Antimicrobial Resistance

Antibiotic resistant bacterial infections are one of the greatest challenges facing modern medicine.

Dr. Margaret Chan, then the Director General of the World Health Organization, warned that bacteria are starting to become so resistant to common antibiotics that it could bring about “the end of modern medicine as we know it.” Speaking to a conference of infectious disease experts in Copenhagen in 2012, Dr. Chan said we could be entering into a “post-antibiotic era”. As a result, she stated, every antibiotic ever developed is at risk of becoming useless, making once-routine operations impossible.

In 2016, an expert panel assembled for the UK Department of Health by the Wellcome Trust concluded that “Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed.”

How antimicrobial resistance happens

Antibiotic resistance was discussed by Alexander Fleming, the discoverer of penicillin, in his acceptance speech for the Nobel Prize in 1945. Resistance has appeared for every class of chemical antibiotics developed to date, and the time for such development is decreasing, with even the newest antibiotics facing issues of resistance within a very few years.

Some bacteria are naturally resistant to many antibiotics, whether by structural features such as the complex cell wall of Gram-negative bacteria, or by growth in external structures such as biofilms. But key to current concerns is acquired antibiotic resistance, which has the potential to transfer between even unrelated bacterial species on mobile genetic elements. This can involve one or more of a number of mechanisms, from blocking access to antibiotics to pumping them out of the cell, and from degrading the antibiotic molecule to changing the structure of its target:

MDR, XDR, PDR…

Multidrug resistance (MDR) refers to bacteria which show resistance to multiple classes of antibiotics. In most cases, this still leaves some windows of vulnerability – some drugs that continue to work, at least for now. But those drugs can be difficult and expensive to use and identifying those drugs which still work is time consuming – time that the patient may not have. While the first appearance of resistance to a particular drug does not mean it is widespread, such spread is both rapid and concerning. The next stage is the much broader form known as extensive drug resistance (XDR), which is increasingly common. But beyond that, resistance to all known effective drugs (pan drug resistance, or PDR) has now been reported in multiple bacterial species on five continents around the world.

Many of the genetic elements controlling antibiotic resistance can be transferred between bacteria. This ability for resistance to spread under the selective pressure resulting from antibiotic use has led to the evolution of the “superbugs,” bacteria resistant to many or even all known antibiotics.

Antibiotic conservation

Attempts to conserve antibiotics through controlled prescribing (known as antibiotic stewardship) are under way, as are efforts to limit their use in non-critical areas such as their widespread use as growth promoters in farmed animals. Unfortunately, these efforts are not as effective as might be hoped due to a combination of commercial concerns, a lack of global adherence to proposed guidelines, and an understandable desire among patients for any potentially effective treatment. There is a very real danger that our ability to find an effective antibiotic to counter routine bacterial infections could soon become a thing of the past.

As more resistant bacteria appear, there are fewer new antibiotics

The issues of antimicrobial resistance are exacerbated by the simple fact that while bacteria adapt to resist antibiotics, antibiotics themselves cannot change. Put simply, “life changes; chemicals don’t”. Once resistance to a particular drug is widespread, the utility of that drug is greatly reduced. While we are losing antibiotics at an alarming rate, the situation is made even worse by the lack of new antibiotics coming to the clinic:

Despite early optimism, bacteria can kill and will continue to kill, unless we have ways to stop them.

New approaches are needed, and are needed now.

Evolution’s approach

Evolution Biotechnologies sees the development of proven, effective phage therapeutics as an essential component of fighting antimicrobial resistance. The company is working to achieve validation of both regulatory and commercial viability by taking a veterinary product through to market, generating revenues before moving on to human therapeutics. This stepwise approach is intended both to minimise risks and to reduce investor dilution, taking products to market in a commercially sustainable way.

Pseudomonas aeruginosa

References

M. Chan (2016). Antimicrobial resistance in the European Union and the world. https://www.who.int/dg/speeches/2012/amr_20120314/en/

L. Czaplewski et al (2016). Alternatives to antibiotics—a pipeline portfolio review. Lancet Infectious Diseases 16: 239-251.S.

D.R.Harper (2018). Introduction: Bacteriophages in the Era of Antibiotic Resistance. In “Bacteriophages: Biology, Technology, Therapy”. https://link.springer.com/referencework/10.1007/978-3-319-40598-8

D.R. Harper, et al (2014). Bacteriophages and biofilms. Antibiotics 3: 270-284.

Karakonstantis, E. Kritsotakis, A. Gikas (2019). Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options. J. Antimicrob. Chemother. doi: 10.1093/jac/dkz401. [Epub ahead of print]

Sukkar E (2013). Why are there so few antibiotics in the research and development pipeline? The Pharmaceutical Journal 291: 520.