Download The Fight Against the Fight Against the Fight Against Bacteria

The Fight Against the Fight Against the Fight Against Bacteria
For most of human history, among the most feared illnesses were acute bacterial infections.
Even the slightest cut, or routine surgery, or seemingly minor illness could result in severe
infections, resulting in significant morbidity and mortality. Following the first successful
treatments with penicillin at Oxford, the threat of bacterial infections was reduced
significantly, allowing for ever-more complex surgical procedures and survival from illnesses
that were formerly lethal. Unfortunately, due to uncontrolled, unnecessary overuse of
antibiotics in medicine and agriculture, through adaptation and genetic selection, antibiotic
resistance soon emerged to even the strongest drugs, leaving us once again in a world where a
minor hospitalization may result in an incurable infection. The rise of these so-called
“superbugs”—organisms resistant to all commonly-used antibiotics—poses a large and
growing threat to human health. As a result, an urgent area of medical research is in the
search for novel antibiotic agents, but progress in recent years has been limited in finding
new drugs.1
Naturally-occurring molecules have been the basis for nearly all of our existing antibiotics,
and other natural products are likely to be even more effective. Like many previous medical
breakthroughs, taking our inspiration from nature has led to a new type of treatment that
shows great promise to kill these dangerous, antibiotic-immune species. Antimicrobial
peptides (AMPs) are molecules that have been used for billions of years by nearly all living
species to combat bacteria. They have been found in fungi, the skin of frogs and even our
own sweat. Promisingly, they function by a very different mechanism from other antibiotics.
Most current treatments target specific biological machinery within bacterial cells, thereby
killing the microbes. Through random mutations and evolutionary selection, however,
bacteria change the structure of this machinery to resist the drugs. In contrast, AMPs work by
destroying a more fundamental part of a bacterium: its cell membrane.2 This membrane is a
complex assembly of molecules that surrounds a cell, controlling its shape and interactions
with the surrounding environment. Disruption of the membrane is lethal to a cell, and because
membrane structure is so complex, bacteria appear to be unable to modify it in response to
these AMPs.
My research aims to address two problems that are hindering the development of AMPs as
important future drug candidates; tuning the selectivity of AMPs to kill bacterial cells while
leaving human cells unharmed, and delivery of the AMP once inside the body to the site of
bacterial infection.
It is irrelevant how effective the AMP is against bacteria if it also poses a threat to the
integrity of our own cells. After all, bleach is a superb antibacterial agent: it’s just a shame it’s also a potent anti-human agent! It is still unknown exactly how these molecules work, so
a fundamental study of their mechanism of action is essential if we are to translate this
understanding into making drugs that do not harm our own cells.
The interaction of AMPs with the cell membrane is difficult to study due to the many
biological processes that occur simultaneously. Our lab thus uses simplified models of
membranes that still contain many of the key structural elements. Then using solid-state
nuclear magnetic resonance (a technique very similar to MRI imaging done in hospitals), we
hope to build a molecular understanding of how the structure of an AMP its ability to
selectively destroy bacterial cell membranes. Using these methods we aim to design artificial
AMPs inspired by natural structures, but which incorporate additional selectivity to target
only bacteria and spare human cells. This work is currently being extended into the biological
realm, where the killing effect of these de novo peptides is being tested against different
species of organisms, ranging from bacterial to human cells. If the results from these
experiments show promise, it would be an excellent validation of the biology-inspired
approach to tackling current, critical global health problems.
Moreover, many drugs are exceedingly potent and safe for use in humans, but are nonetheless
clinically useless because they cannot be absorbed into the bloodstream, or are broken down
by the body before they can reach the infection. This is the case for current AMPs, which,
because of their structural similarity to proteins, are quickly destroyed by the body. A second
aim of our research is therefore to design nanoparticle transporters that encapsulate and
protect AMPs in the body, while transporting them to the desired site of action.3 At a
molecular level, the release of other encapsulated drugs is also being explored. If release can
be induced by a change in acidity or application of light, this could have great implications
for enhanced targeting in cancer research and photodynamic therapy respectively.
Improving on defence mechanisms that nature has spent millions of years designing is a
challenging task, but one with the potential for large clinical impacts. Given the grave
dangers posed by modern superbugs, however, further basic research underpinning this
progress is vital. I hope that my research into the fundamental behaviour of antimicrobial
peptides can be taken from the bench to the bedside, aiding the production of future drugs of
great clinical importance and addressing one of our contemporary challenges to survival.
References
1. Clin Infect Dis., 52 suppl., 2011.
2. J. L. Fox, Nature Biotechnology, 2013, 31,379–382.
3. M. C. Orwick, P. J. Judge, A. Watts et al, Angewandte Chemie International Edition, 2012, 51, 4653-4657.