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We know that our bodies have their own defence mechanism against invading microbes (pathogens such as bacteria and viruses). This defence mechanism is in the form of antibodies, which are proteins (long chains of amino acids) — the antibodies destroy the pathogens, or, at least, most of the time. This defence mechanism is strengthened by man-made drugs — antibiotics — which kill bacteria (not viruses).
However, the pathogens are smart. Over time, they have developed resistance to drugs. This antimicrobial drug resistance (ADR) is now so serious that it has come to be recognised as a major killer. Take, for example, the tuberculosis-causing Mycobacterium tuberculosis, which is proving to be too slippery for the TB vaccine Bacillus Calmette Guérin, or BCG. Some research papers say that about 700,000 people die annually because of ADR; this number is estimated to swell to 10 million by 2050.
What’s the solution?
Scientists are now turning to a less-recognised line of defence known as ‘antimicrobial peptides’, or AMPs. Peptides are small chains of amino acids. AMPs are produced by human bodies, as also other living beings. Today, about 5,000 AMPs are known, catalogued. AMPs are proving to be smarter than invading pathogens (at least for now). The pathogens enter healthy cells and use the chemicals to multiply, destroying the cells in the process. AMPs attach themselves to cell membranes of bacteria or virus and prevent them from entering healthy cells. This happens because the cell walls of pathogens are negatively charged, whereas AMPs are positively charged — the attraction between unlike charges enables AMPs to cling to the membranes.
“The use of antimicrobial peptides (AMPs) provides an attractive solution to combat the problem of antimicrobial resistance,” says a December 2022 research paper authored by scientists from Guru Granth Sahib World University, Punjab, and Amity Institute of Biotechnology, Rajasthan, and published in the magazine Microbiological Research. “These peptides are effective, broad-spectrum antimicrobials that establish themselves as new therapeutic agents, and hold potential to kill gram-negative and gram-positive bacteria, fungi, enclosed viruses, and even mutated or malignant cells,” the authors say.
The point to note is, unlike antibiotics, AMPs are effective against viruses too. There is recent evidence that several AMPs of human, insect and plant origin work against a broad range of viruses, says the paper, which indeed was about the potential of AMPs to fight Covid-19.
Amir Pandi et al of multiple German research institutions note in a paper awaiting peer review that, despite the looming threat of ADR pathogens, there is not enough research on developing antimicrobial drugs. “While more than 4,000 immuno-oncology compounds were in clinical trials in 2021, only 40 antimicrobials (of which none is active against multi-drug resistant gram-negative bacteria) were subjected to clinical studies, highlighting the urgent need to increase the development of novel antimicrobial compounds,” the paper says.
Well, the world will turn to AMPs, which are described as “next-generation antimicrobials”. But the problem is, how to produce AMPs. It is possible to chemically synthesise AMPs. Another option is to take the DNA in organisms and coax it to produce the peptides. But both are time-consuming, costly and with no guaranteed output.
Designer AMPs
The German researchers have reported a novel method, called ‘cell-free protein synthesis’ (CFPS), which involves in-vitro transcription (making RNA from DNA) and translation (making peptides from RNA). In other words, the peptides are made outside living cells.
This method, the scientists say in the paper, “can help overcome potential cellular toxicity effects, and open up the way for rapid, small-scale production of several hundreds of peptides from linear DNA in parallel.”
Describing the research, the paper says, “We combined deep learning and CFPS for de novo-design, rapid production and screening of AMPs at small scale within 24 hours, and less than $10 per individual AMP production assay (excluding cost for the DNA fragment).”
Having explored around 500,000 theoretical sequences, the researchers screened 500 AMP candidates to identify 30 functional AMPs, which are completely unrelated to natural sequences. Six of these AMPs “exhibited high antimicrobial activity against multidrug-resistant pathogens, showed no emergence of resistance and only minimal toxicity on human cells.”
AMPs are still in the realm of R&D, but show promise. Dr Subramanian Swaminathan, Director–Infectious Diseases, Gleneagles Global Health City, Chennai, feels Indian industry should undertake more research into this “exciting area”. Swaminathan told Quantum that with the sole exception of enfuvirtide, for HIV infections, there is no AMP drug in the market yet. He observed that good work is on at public research labs, but not much in pharma industry. In 2019, Indian Institute of Science, Bengaluru, and MS Ramaiah Medical College came up with a peptide, named Omega76, against the ESKAPE family of bacteria, but there has not been much progress since.
Swaminathan observed that industry tended to ignore the anti-microbial segment because it is return-negative. As a result, the problem is growing bigger. AMPs can be a solution. However, there is need for proper clinical trials, he cautions. After all, these are biological products and there will be long-term consequences, both intended and unintended.
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