‘Youngest' antibiotic kills bacteria via a new two-step mechanism
Scientists at Utrecht University have discovered a new mechanism of how antibiotics kill bacteria. The antibiotic teixobactin uses a dual molecular strategy: it blocks the bacterial cell wall synthesis and destructs the cell membrane, the researchers write in the scientific journal Nature. The new insights could enable the design of powerful antibiotics against which bacteria do not readily develop resistance.
Antibiotics are used to treat bacterial infections and are among the most widely used drugs worldwide. They are vital to combat many infections in the respiratory and intestinal tracts, as well as various skin conditions. However, bacteria have become increasingly resistant to antibiotics, as most antibiotic classes currently used in clinics have been used for about half a century. In 2015, scientists from Boston (USA) successfully isolated teixobactin, the first novel antibiotic discovered in about 40 years.
Now, seven years after its discovery, a large international team led by Associate Professor Markus Weingarth from Utrecht University, found out at a molecular level how teixobactin kills bacteria. The team used several advanced structural biology techniques and collaborated with the discoverers of teixobactin Prof. Kim Lewis of Northeastern University in Boston and the company Novobiotic.
Teixobactin uses a unique killing strategy.
"Bacteria need a special lipid called lipid II to build their protective envelope around them. We show at atomic level that teixobactin targets and sequesters lipid II. Afterwards, teixobactin and lipid II together form long fibrils on bacterial cell membranes," says Weingarth. "Gradually, this creates a kind of valley in the landscape of the cell membrane, which then breaks down and damages the membrane." The Utrecht researchers turned out to have found a biomolecular mechanism that was unknown to science until now. "It is a unique killing strategy."
Better drugs against certain respiratory diseases
PhD candidate Rhythm Shukla, who is the first author of the study, and Weingarth used a technique called solid state nuclear magnetic resonance (ssNMR) to solve the complex formed by teixobactin and lipid II at atomic level in lipid membranes. Subsequently, the team was able to visualise the fibrils in membranes and directly in bacteria using several microscopy techniques.
Weingarth: "Our study marks the first time this powerful approach is used to elucidate the action of membrane-active antibiotics. Antibiotics that act on the cell membrane are very difficult to understand. Now that we know how teixobactin works, it will be possible to rationally design better drugs against pneumonia, tuberculosis, or infections with MRSA bacteria. For all of these respiratory diseases, resistance to current antibiotics is a huge problem."
Rhythm Shukla, Francesca Lavore, Sourav Maity, Maik G.N.Derks, Chelsea R. Jones, Bram J.A. Vermeulen, Adéla Melcrová, Michael A. Morris, Lea Marie Becker, Xiaoqi Wang, Raj Kumar, Joâo Medeiros-Silva, Roy A.M. Van Beekveld, Alexandre M.J.J. Bonvin, Joseph Lorent, Moreno Lelli, James Nowick, Harold D. MacGillavry, Aaron J. Peoples, Amy L. Spoering, Losee L. Ling, Dallas E. Hughes, Wouter H. Roos, Eefjan Breukink, Kim Lewis, and Markus Weingarth
Nature, 3 August 2022, doi: 10.1038/s41586-022-05019-y