A corneal infection can destroy the transparent front window of the eye, causing blindness in roughly 2 million people each year. Existing antibiotics are losing their power against these infections because bacteria are evolving resistance, and some infections involve multiple organisms that standard drugs cannot handle. This researcher has already built hybrid antimicrobial peptides—short proteins that punch holes in bacterial membranes—by combining two natural human defence molecules. Now they are using artificial intelligence to design improved versions of these peptides, then testing them against bacteria and fungi in the lab and in animals. They are also wrapping the peptides in biodegradable nanoparticles and a fluid gel to keep them stable long enough to work. If successful, this approach could produce a new class of topical eye treatments that bypass existing antibiotic resistance mechanisms. Because the peptides attack the physical structure of microbial membranes rather than a single biochemical target, bacteria are less likely to develop resistance against them. The same platform could eventually be adapted for infections elsewhere in the body, offering a potential solution to the global crisis of antimicrobial resistance.
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Cornea - the transparent front window of the eye - serves as a critical structure to normal vision and ocular surface defence. Damage to the cornea can lead to significant ocular pain and permanent scarring with resultant visual impairment or blindness. Infectious keratitis (IK), or commonly known as corneal infection, is the leading cause of corneal blindness globally. It has caused ~5 million cases of blindness and is estimated to affect ~2 million people each year. Affected patients are usually debilitated by pain and visual impairment, and they often require long-term hospital admissions for intensive antibiotic treatment. However there has been a growing concern on the declining antibiotic efficacy due to emerging antimicrobial resistance (AMR), polymicrobial infection (i.e. infection caused by more than one organism), and limited treatment options. In addition, AMR has emerged as a global health threat and is estimated to cause over 1 million deaths annually. These issues highlight the urgent need for new effective antimicrobial treatment for tackling IK and AMR. Antimicrobial peptides (AMP), or host defence peptides, form an important component of the first-line defence in all living organisms (including human). They are made up of amino acids (the basic structural units of protein) and can be found in various parts of the human body, including the eye. They have recently shown promise as potential treatment due to their unique antimicrobial activity against a wide range of organisms, such as bacteria, fungi, parasites, and viruses. These positively charged AMP usually kill the pathogens by disrupting the negatively charged membrane (outer surface coating) of the organisms. However, the clinical utility of AMP is limited by several issues such as potential toxicity to human cells, instability in certain body environment, susceptibility to breakdown by human / bacterial enzymes, and cost. Recently, I have developed efficacious and safe hybrid AMP, based on rational combination of human beta-defensins (HBDs) and human cathelicidin (LL37), for treating IK. I have also developed highly accurate artificial intelligence (AI) algorithms in predicting the activity of AMP. The overarching goal of my MRC Fellowship is to develop novel AMP for treating a range of IK and tackling AMR, using AI and novel drug delivery systems. During the first stage, I will develop novel peptide language-based generative AI models to help optimise my human-derived hybrid AMP and potentially discover new AMP. I will then test the antimicrobial activities, safety and mechanism of action of the improved AMP against a range of bacteria and fungi related to IK and AMR, through both laboratory and ethically designed animal studies. In the second stage, I will explore various formulation strategies to enhance the efficacy, safety and stability of my AMP, using novel fluid gel technology (Gellan) and biodegradable nanoparticles/polymers. I will perform a series of experiments, including laboratory and animal experiments, to characterise and examine the properties, efficacy, safety and stability of my formulated AMP. These represent the essential steps before advancing the AMP therapy to human clinical trials. The proposed experiments will be conducted collaboratively in the UK, the US, and Singapore. Successful development of these AMP can bring new exciting therapies to the clinic, ultimately benefitting patients with ocular and potentially non-ocular infections. This may also offer a potential novel solution to AMR.
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