The entire Planet Earth finds itself on the brink of certain apocalypse. Nothing – not even an atom bomb – can halt the invading Martians. Only one thing saves the planet: bacteria, which sicken and kill the Martians.
In his 1898 science fiction novel, The War of the Worlds, H. G. Wells recognized that despite possessing the most powerful anti-personnel arsenal, humans (and aliens) remained powerless against bacterial infection. Though we humans have since developed an array of weapons to battle against this age-old enemy, the micro-organisms are fighting back, developing protection against the arms we’ve stockpiled by becoming increasingly resistant to many types of antibiotics.
But the battle against antibiotic-resistant bacteria and fungi may not be lost just yet. By combining the components of two different types of weapons used by an organism’s innate immune defense system, a team of scientists at the Weizmann Institute of Science has managed to devise a blueprint for a more powerful weapon, hoping that this will lead the way to new and more effective antibiotics.
The problem with conventional antibiotics stems from their mode of action: They target specific objectives within the bacteria or fungi, such as enzymes or DNA. Instead of killing the enemy, these antibiotics may only cause them injury, which can buy them enough time to pass down information to future generations. The result is a “resistance movement” of bacteria better able to defend themselves against future attacks. By contrast, two types of weapons that are produced in nature physically destroy the cell membranes of bacteria and fungi, wiping the enemy out completely. But there is one catch: Most of these weapons are active against either bacteria or fungi alone, making it hard to manipulate them for therapy.
If only a way could be found to make a multipurpose weapon that attacks bacteria as well as fungi, yet is simple and resistance-free. As reported in the Proceedings of the National Academy of Sciences (PNAS), Prof. Yechiel Shai, and Ph.D. students Arik Makovitzki and Dorit Avrahami of the Biological Chemistry Department seem to have succeeded in doing just that.
The innate immune systems of organisms possess two types of weapon; both of them provide protection against offensive microorganisms, but they differ in their means of attack. The first is a group of protein fragments called antimicrobial peptides (AMPs), and their chief characteristic is a specific complement of amino acids that imbues them with a net positive charge. AMPs are produced by all organisms and are mainly active against bacteria, whose cell walls have a net negative charge that attracts the AMPs to their surface like a magnet. The second group of weapons – called lipopeptides – produced only in bacteria and fungi, is mainly designed to target pathogenic fungi. Lipopeptides do not carry a positive charge, but they contain a high percentage of fatty acid chains, rendering them highly hydrophobic (water hating) – a property that makes their antimicrobial activity more potent.
Says Shai: “We asked, what would happen if we could combine these two features into one structure?” Through this basic research question, the team succeeded in improving on nature by designing synthetic lipopeptides that contain both key properties – positive charge and hydrophobicity. By altering the length of the fatty acid chains and the sequence of the positively charged amino acids, they were able to create an array of weapons – some active against both bacteria and fungi, others targeting just one or the other, each with a different potent activity and species specificity. As if this were not enough, they managed to design these new synthetic peptides with only four amino acids, as opposed to between 12 and 50 found in the natural forms.
Shai: “We were surprised to find that despite the small size of these molecules, they are still able to exert antimicrobial activity that is just as effective as the longer, naturally occurring forms – or even more so.” The next question to explore is: How does such a short molecule retain its potency? “These findings are very exciting,” explains Shai. “This basic research question could open up a whole range of potential applications. The short length makes the synthetic peptides attractive for use in drugs, as they would be easier and cheaper to synthesize, less prone to resistance and designed to target a large range of bacterial and fungal infections.”
At the moment, many native lipopeptides are not overly picky about which cells they attack, and they are therefore toxic to mammalian cells, too. Thus the next challenge is to design these molecules to be safe when administered to humans. The Weizmann team is optimistic as, while designing the synthetic lipopeptides, they replaced some of the amino acids with their “mirror image” form, a change that caused the peptides to degrade over time, preventing their accumulation in the body and reducing toxicity.
Prof. Yechiel Shai’s research is supported by the Robert Koch Minerva Center for Research in Autoimmune Disease; the Prostate Cancer Research Fund; the estate of Julius and Hanna Rosen; and the Eugene and Delores Zemsky Charitable Foundation Inc. Prof. Shai is the incumbent of the Harold S. and Harriet B. Brady Professorial Chair in Cancer Research.