Published: 27 August 2024
In an exciting breakthrough, researchers from the Institute for Infection and Immunity have successfully transformed a weak antimicrobial peptide (AMP) into a growth-enhancing peptide for faster tuberculosis diagnosis.
The team published results from a clinical trial confirming the peptide's effectiveness. However, in a surprising twist, they also discovered a peptide variant with strong inhibitory activity, potentially leading to a new drug development pathway.
They say that this remarkable journey has come "full circle", starting from an AMP, evolving into a growth-stimulating peptide for diagnostics, and returning to a powerful AMP.
Engineering new antimicrobial peptides for TB
Dr Kai Hilpert, an expert in AMPs, and Dr Tim Bull, a specialist in mycobacteria, have engineered new AMPs for tuberculosis. By rearranging the sequence of amino acids - the key 'building blocks' of peptides - the researchers have created two distinct sets of AMPs. One set accelerates the growth of Mycobacterium tuberculosis, while the other dramatically slows it down.
"This is a full circle story where, with just one change to the order of the amino acids in a peptide that can help speed up TB diagnosis, we have created a strong antimicrobial peptide that could be the backbone of a future treatment"
- Dr Kai Hilpert, Associate Professor (Reader) in Infection and Immunity -
Persistent global health threat
Tuberculosis remains a persistent global health threat, with the highest mortality rate among infectious diseases and an estimated 10 million new cases worldwide annually.
The slow-growing nature of TB bacteria has traditionally meant lengthy diagnosis times - it takes up to 30 days to confirm its presence in patient samples and in a subsequent test to determine drug resistance. This delay significantly impacts treatment plans and patient outcomes.
Revolutionising TB detection
The growth-accelerating AMPs developed by the researchers promise to revolutionise TB culturing from patient samples, enabling faster diagnosis than ever before.
In a groundbreaking clinical trial involving 255 samples from 155 patients with suspected TB, Dr Bull used two growth peptides in conjunction with their newly-developed sample processing kit containing AMPs. This innovative approach reduced the average time to confirm the presence of TB by seven days, with a remarkable 46% higher rate of confirmed TB compared to standard culturing methods.
Dr Hilpert then did a deep dive into the sequence of one of the growth-stimulating peptides, Peptide 14D, by substituting all of the amino acids with 19 other amino acids to create 171 different forms, and analysed the impact each rearrangement had on Mycobacterium tuberculosis growth.
'Supercharged' antimicrobial peptide
“This revealed a ‘supercharged’ form of Peptide 14D that reduced the time taken for a positive result to be confirmed by another 25 hours. Adding this ‘supercharged’ AMP to samples mean that patients, and their close-contact family and friends, can get access to a more accurate and faster diagnosis that better fast tracks their access to treatment to reduce the spread of infection, or enable them to go home from hospital sooner.”
- Dr Kai Hilpert -
The ‘supercharged’ AMP is thought to aid faster growth by interacting with the membrane that lines the outside of the TB bacteria, putting it into a ‘confused’ state where the normal signals telling the bacteria to remain in a quiet, non-growing environment don’t work anymore. This ultimately suppresses the inhibitory signal and tells the bacteria to grow really fast.
New TB drug on the horizon
But just one change to the amino acid order of Peptide 14D surprisingly produced a strong AMP that dramatically slowed-down the rate of bacteria growth. More research is needed to determine how this opposing AMP works. The team say one possible explanation is that it could also be linked to an extreme impact on the bacteria membrane, but that it causes a reduced ability for it to produce energy and interrupts a cascade of signals that put the bacteria into an extended non-growing state.
The team now plan to see how this strong AMP can be harnessed as a template for a new type of drug against TB.
Learn more about St George’s infection and immunity research