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Antibiotic-resistant bacteria (e.g., hospital superbugs) pose a particularly acute healthcare challenge, and strains that are resistant to an increasing number of antimicrobial agents in clinical use have now been identified. At the same time, the discovery of new antimicrobial agents is declining, and we are facing an “antibiotic crisis”. As a result, the World Health Organization has recognized antimicrobial resistance as an increasingly serious threat to global public health which requires action across all government sectors and society.
To design next-generation treatments, we need to understand the science of how antibiotic agents operate at the molecular level. Some antibacterial agents kill microorganisms by disrupting directly their cell membranes, which leads to leakage and death. It seems to be difficult for microorganisms to reengineer their membrane structure to resist such agents, without compromising their own integrity. As a result, design of drugs which target microbial membranes is seen as a promising strategy.
Our team from the Science and Technology Facilities Council (STFC) and IBM Research at the Hartree Centre seeks to couple ultra-large-scale computer simulation with AI to study processes in cell membranes at the molecular level. We have shown, using computer simulations, that mechanical stresses on cells can affect the apparent potency of simple antibiotics. These stresses can arise from interactions with the environment, between cells, and with the extracellular matrix, leading to sophisticated feedback mechanisms between membrane tension and cellular processes. We discovered a relationship between membrane tension, generated by osmotic pressure or environmental forces, for example, and chemical interactions of antimicrobial agents, with both working to disrupt the bacterial membrane. Our approach combines physical and chemical views of the process, and the insights are starting to reveal new aspects of how antibiotic agents work at the cellular and molecular levels. The results, obtained through atomic-scale molecular dynamics simulations of a lipid bilayer as a mimic of the cellular surface, have been demonstrated with several lipid compositions and appear to be general, although quantitative details differ. The findings imply that the potency of antimicrobial peptide is not a purely intrinsic chemical property and, instead, depends on the mechanical state of the target membrane. The findings are reported today in Physical Review Letters.
A snapshot of a simulated cell membrane at the molecular scale showing lipid molecules with head groups (pink spheres) and tails (pink tubes). Under tension, peptides or protein fragments (green coils) induce membrane rupture allowing water (blue spheres) to flood the channel.
Looking to the future, improved understanding of the impact of the mechanical state of cells on antimicrobial peptide potency using better mimics of bacterial membranes, such as cardiolipin, is required to elucidate the mechanisms of bacterial drug resistance that develop through changes in lipid composition. More broadly, how antibiotic molecules penetrate and disrupt bacterial membranes is closely related to the mechanisms of membrane permeation required to deliver drugs to targets inside the cell. Both require the membrane barrier to be traversed. The results reported here may therefore have a wider impact on drug delivery across cellular barriers before they reach the circulatory system.
Modulation of Antimicrobial Peptide Potency in Stressed Lipid Bilayers
Valeria Losasso,1 Ya-Wen Hsiao,1 Fausto Martelli,2 Martyn D. Winn,1 and Jason Crain2
1 Daresbury Laboratory, STFC, Daresbury, Warrington, England WA4 4AD, United Kingdom
2 IBM Research, Hartree Centre, Daresbury, England WA4 4AD, United Kingdom
Phys. Rev. Lett. 122, 208103