Antimicrobial agents: past, present & future

Donkey teeth, mouldy bread and the ongoing battle against infection.

Dermot McGrath

Posted: Monday, March 1, 2021

Harminder Dua CBE, FRCS,
FRCOphth, PhD

The cycle of history has much to teach us when it comes to understanding the evolution and development of antimicrobial agents in the age-old fight against infectious diseases, according to Harminder Dua CBE, FRCS, FRCOphth, PhD.
In a presentation on the past, present and future of antimicrobial agents, Prof Dua outlined how ancient civilisations used a wide variety of animal, mineral and plant products to try to treat infections, some of which have surprisingly strong parallels to modern therapies.
“It is well known that the past determines the future, but to that I would add that the past is often the future,” said Prof Dua at the 11th EuCornea Congress. For example, ancient Egyptian artefacts record at least 95 prescriptions for various eye diseases, explained Prof Dua.
“There were several extracts from plants and from animals that were used for a variety of applications and indications – garlic, resin, leaves, minerals and extracts from crocodile or flies, bone marrow from donkey teeth and even healthy pigs’ eyes which were mixed with ochre and honey to make concoctions to be poured into the eye or ear,” he said.
Prof Dua said that while many of these concoctions may seem rudimentary or eccentric from a modern perspective, we should not be too hasty to judge our ancestors.
“Ancient civilisations used extracts from donkey teeth and today we are using stem cells extracted from dental pulp for tissue regeneration. The ancient Egyptians also applied mouldy bread to infected wounds, not knowing that this would one day lead to the game-changing antibiotic penicillin,” he said.
The 20th Century saw a number of important landmark breakthroughs in combating infection with the discovery of sulphonamides, penicillin, aminoglycosides, macrolides, and agents such as tetracycline, chloramphenicol and cephalosporin, said Prof Dua.
“In the 1950s and 1960s we had a rich harvest of antibiotics such as colistin, vancomycin and, most noteworthy for ophthalmologists, fluoroquinolones, which are still the most popular antibiotics we use today. The introduction of azithromycin was also a game-changer in the trachoma eradication programme,” he said.
The picture became more sombre in the 1980s and 1990s as drug resistance started to emerge as a major problem.
“The magnitude of this problem is so immense that in 2016 the O’ Neill Report commissioned by the UK government suggested that without action, antimicrobial resistance will cause the deaths of 10 million people a year by 2050.
This problem is compounded by the fact that the number of antibiotics produced dropped from 16 in the years 1983 to 1987 down to only two between 2008 and 2012,” said Prof Dua.
The main reason for the decline in drug production stems from the lack of profitability in developing new antibiotics.
“For every 100 drugs developed only one or two make it to market. At $2.5 billion spent developing each antibiotic drug, antibiotics are not profitable enough to recoup losses. My take on this is that governments have to join hands with industry in combating antimicrobial resistance and in developing new agents,” he said.
Highlighting some of the more interesting agents currently under development, Prof Dua cited Teixobactin, a new class of antibiotics which has a novel mechanism of action by binding to lipid II and lipid III, important precursor molecules for forming the cell wall, and Cefpodoxime, which has activity in the presence of some beta-lactamases of Gram-negative and Gram-positive bacteria.Another exciting breakthrough is the antibiotic Halicin, the first drug of its kind to be discovered using artificial intelligence (AI).
“It can learn new patterns unknown to human experts. It has a novel mechanism of action of disrupting the flow of protons across a cell membrane. In initial animal tests it also seemed to have low toxicity and to be robust against resistance,” he said.
A lot of research has also been devoted to antimicrobial peptides (AMPs), which are naturally occurring eukaryotic analogues of antibiotics, said Prof Dua.
“They are very effective against a range of organisms, namely Gram positive and negative bacteria and fungi and enveloped viruses with a low tendency for resistance. Because of the mechanism of action there is very little chance for the organism to develop resistance to these agents,” he said.
AMPs may turn out to be more effective for ocular use in combination therapies with antibiotics, said Prof Dua. He cited a recent publication by his group which showed that vancomycin, which is normally not very effective against pseudomonas, can be combined with a peptide (FK16) for greater efficacy than if using either agent individually.
Prof Dua also highlighted the promising work of Mario Nubile and Leonardo Mastropasqua in creating a stromal lenticule from a donor eye that can then be loaded with various chemicals or molecules for therapeutic effect before being implanted back into the eye.
“The lenticules can be taken and decellularised and impregnated with microparticles or nanoparticles for antimicrobial and wound healing effects and tissue regeneration. This will deliver a sustained delivery of the drug at the site of action,” he concluded.