Cracking bacteria’s defences

By Rosaria Carbone

Since the discovery of penicillin by Alexander Fleming almost a century ago, more than 150 antibiotics have been developed, saving countless lives. Nevertheless, bacterial evolution has kept pace, rendering many of these drugs ineffective. Newly discovered antibiotics often lose their effect within a few years as bacteria develop resistance mechanisms. Consequently, higher doses are required to kill the bacteria, but beyond a certain threshold, antibiotics become harmful to humans. As a result, antibiotic resistance has become one of the most serious global health threats of our time.

How can this resistance be overcome? Supported by an ERC Consolidator Grant, Robert Vácha believes that antimicrobial peptides (AMPs) are a promising solution. These tiny molecules, found in many living organisms, were discovered around 30 years ago. They form part of our immune system and act as a first line of defence using different mechanisms of action to fight bacteria and viruses.
 

Small molecules not yet understood
 

Vácha is studying one such mechanism, in which a specific class of AMPs kills bacteria by perforating their outer lipid membrane. His challenge is to gain a deeper understanding of this process that, although highly effective, remains unclear. While they can efficiently disrupt the bacteria’s protective shield, peptides may also create pores in human cell membranes, which represents a serious problem. 

Peptides are short chains of amino acids, and it is essential to understand the role of each component. Even a single change in the sequence of amino acids can drastically alter the peptide’s behaviour. 

‘My goal is to identify the key properties that allow peptides to breach bacterial membranes. This requires investigating the activities of the peptides at the molecular level. Thanks to the ERC funding, I can combine computer simulations with laboratory experiments in a systematic approach,’ Vácha says. ‘If we understand the synergetic action of all the amino acids, we will be able to design peptides that selectively attack pathogens without damaging human cells.’ 
 

A highly interdisciplinary effort
 

A physicist by training, Vácha has brought together chemists, biologists, computer scientists, microbiologists, and biochemists and collaborates with medical researchers for in vivo experiments. Based at CEITEC, Masaryk University, in the Czech town of Brno, the team is truly international, with members from the Czech Republic and from across Europe, the United States and India. 

The combination of different expertise and methods allows researchers to observe at the molecular scale how peptides are able to crack membranes. Computer simulations are used to test different peptide variants and to predict their interactions with bacteria’s protective layer. 

‘What I like about this approach is that we can tune the peptide. If it doesn’t work against a particular bacterium, we investigate why it fails and then modify it to make it effective. There are many possible manipulations at the molecular level, and this is fascinating to me,’ Vácha notes. 

The most promising peptides identified through computational design are subsequently tested experimentally - initially against resistant bacteria and human cells, and later, through collaborations, in mice. 

‘I’m very happy to see that our efforts have already led to exciting results. We have produced peptides that, in early experiments, succeeded in killing a resistant bacterium, Acinetobacter baumannii, which is responsible for various skin and lung infections, at very low concentrations and without harming other cells,’ Vácha says. 

According to him, the ERC’s high-risk, high-gain approach has been essential for this work, as his initial hypothesis initially faced significant scepticism.
 

A therapeutic potential for respiratory diseases
 

Building on this achievement, Vácha has recently secured an ERC Proof of Concept Grant to carry out larger-scale in vivo experiments, aimed at confirming the initial findings and generating more robust data. In close consultation with clinicians, he has chosen to focus preclinical testing on lung infections, conditions that are both relatively common, particularly among older people, and notoriously difficult to eradicate. These infections frequently occur in hospital settings, for example, in patients requiring assisted breathing via tubes or ventilators. They are often caused by antibiotic-resistant strains, making treatment particularly challenging. 

‘If experiments on mice are successful, the next step will be to create a spin-off to start the clinical trials. The AMPs disruption of the pathogen’s lipid membrane is a mechanism that complicates the development of resistance,’ Vácha explains. 

‘This advantage could prove decisive in tackling infections on which existing drugs are no longer effective. We have observed a steady increase in Europe of multi-resistant bacteria that do not respond to several treatments, and this is extremely concerning.’ 
 

Long-term perspectives
 

These newly developed AMPs could represent a new class of therapeutics, with the potential to attack multi-resistant bacteria, viruses and even cancer cells. By moving beyond traditional antibiotic strategies, Vácha aims to open a new and much-needed pathway in the fight against drug-resistant infections - one that could reshape how dangerous pathogens are treated in the future.

Vácha is also upbeat about future research developments on peptides and aims to advance his work to fully uncover their other mechanisms of action. For example, peptides can also induce membrane curvature or fusion, which can be utilised in the targeted delivery of drugs inside the cells.

Biography
 

After obtaining his PhD in the field of molecular dynamics simulations at Charles University, Prague, Robert Vácha moved to a post-doctoral position at the University of Cambridge, and later to Lund University in Sweden. He then returned to Czech Republic where, since 2017, he leads the protein-membrane and protein-protein interactions group at the Central European Institute of Technology (CEITEC) in Masaryk University.