In the past few decades, many Gram-negative bacteria have acquired multi-drug resistance, compounding the global threat to public health. Many pathogenic bacteria, including those that cause dysentery, pneumonia, and sepsis, are classified as Gram-negative bacteria. In addition to preventing the entry of the violet Gram stain (which gives these bacteria their name), the outer layer of these bacteria also excludes many antibiotics that would otherwise have contained their spread.

A thin peptidoglycan cell wall sandwiched between a distinctive outer membrane made of carbohydrate and protein conjugated fats, and an inner cytoplasmic bilayer forms the composite outer barrier of Gram-negative bacteria. A new study published in the journal Nature, shows Gram-negative bacteria coordinate the assembly of their cell wall and outer membrane. This new mechanistic insight uncovers a potential vulnerability that could facilitate the design of next-generation antibiotics.

The characteristic outer membrane in Gram-negative bacteria maintains cellular integrity and is critical for its growth and survival in challenging environments and depends for its activities on outer membrane proteins (OMPs). A multi-protein complex called BAM (beta-barrel assembly machinery) that includes a protein called BamA, helps insert OMPs into the outer membrane. Being on the bacterial surface and serving a pivotal role in survival, makes BamA a promising target for antibiotics that inhibit Gram-negative bacteria.

The new article (“Peptidoglycan maturation controls outer membrane protein assembly”) shows BamA’s ability to introduce new proteins into the outer membrane is strictly controlled by the cell wall beneath it, rendering OMP synthesis in the outer membrane responsive to peptidoglycan maturation in the cell wall.

The study results from a collaboration among the laboratories of Waldemar Vollmer, PhD, a professor at the Centre for Bacterial Cell Biology at Newcastle University, and Colin Kleanthous, PhD, a professor of biochemistry at the University of Oxford.

Colin Kleanthous, PhD, a professor of biochemistry at the University of Oxford, is a co-senior author of the study.

Kleanthous said, “We never suspected that Gram-negative bacteria were so reliant on the cell wall to coordinate growth of the outer membrane. Disrupting this cross-talk would literally ‘open up’ Gram-negative bacteria, making them vulnerable to antibiotics that the outer membrane otherwise excludes.”

Waldemar Vollmer, PhD, a professor at the Centre for Bacterial Cell Biology at Newcastle University, is a co-senior author of the study.

Vollmer explained, “Bacteria are tiny yet have a very high internal pressure, like a car tire. They have a strong cell wall to withstand this pressure and prevent them from bursting while still allowing them to grow and divide. What we have revealed for the first time is how the process of cell wall expansion is linked to that of the outer membrane beyond it, as the bacteria grow.”

Earlier studies have shown that as E.coli grow, old OMPs move toward the polar ends of the bacteria. How this partitioning occurs has been unclear, until now. The new study uncovers that the age of peptidoglycans in the cell wall determines the biogenesis of OMPs in the outer membrane. The researchers showed mature peptidoglycan that occurs primarily at the polar ends of the bacteria, binds BAM components and stops OMP biogenesis, whereas newborn peptidoglycan found at indentations where the bacteria divide, bind BAM poorly and allow the greatest insertion of OMPs into the outer membrane.

Financial support for the study came from the European Union’s Horizon 2020 program, the European Research Council, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the Medical Research Council.

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