A new study published today in Nature has discovered a potential Achilles heel in the protective layers that surround Gram-negative bacteria, which could help in the creation of next-generation antibiotics. Professor Waldemar Vollmer and Dr Federico Corona of Newcastle University, along with Professor Colin Kleanthous and Dr Gideon Mamou of the University of Oxford's Department of Biochemistry, have discovered that Gram-negative bacteria rely on the cell wall to synchronize the formation of the outer membrane.
Antimicrobial resistance (AMR) has been named one of the top ten worldwide public health problems by the World Health Organization (WHO). Antibiotic resistance has already developed in some microorganisms. Gram-negative bacteria that cause pneumonia and sepsis, such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, are particularly hazardous. Because their outer membrane is located outside of the cell wall, it is immune to many medicines that would normally target it.
The findings show that the cell wall, which is made up of a strong substance called peptidoglycan, has a surprising amount of control over where new proteins are introduced into the outer membrane by BamA, an important biogenesis protein. This aids bacteria in coordinating these layers, which is essential for their growth.
"Bacteria are microscopic but have a very high internal pressure, like a car tyre," explains Professor Vollmer of Newcastle University Biosciences Institute's Centre for Bacterial Cell Biology. They have a thick cell wall that allows them to endure the strain and avoid bursting while still allowing them to grow and divide. For the first time, we've shown how the process of wall growth is related to that of the outer membrane outside it as they grow."The age of the mesh-like peptidoglycan – made up of amino acids and sugars – was discovered to be the most important element. The synthesis of new outer membrane proteins is entirely shut down by 'old' peptidoglycan, which is found largely at the poles (ends) of cells.
The most amount of outer membrane expansion is allowed by 'new' peptidoglycan, which is found largely at places where cells are going to divide. Bacteria maintain tight control over both cell envelope layers thanks to this basic yet elegant process."We never imagined Gram-negative bacteria were so reliant on the cell wall to coordinate growth of the outer membrane," said Professor Kleanthous of Oxford. Disrupting this cross-talk would essentially 'open up' Gram-negative bacteria, exposing them to drugs that would otherwise be blocked by the outer membrane."
Horizon 2020, the European Research Council, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the Medical Research Council all supported the research.
