Penicillin-Binding Proteins (PBPs) are a group of proteins in bacteria defined by their ability to bind with penicillin. This interaction is the basis for the function of many widely used antibiotics. PBPs are involved in the final steps of building the bacterial cell wall, a structure necessary for the microbe’s survival and reproduction. Inhibiting these proteins leads to defects in the cell wall, causing the bacterial cell to die.
Understanding Penicillin-Binding Proteins
Penicillin-binding proteins are enzymes located within the bacterial cytoplasmic membrane and the periplasmic space. This binding was later understood to be an interruption of their normal enzymatic job. All bacteria possess PBPs as part of their standard cellular machinery, highlighting their role in fundamental life processes.
Bacteria have multiple classes of PBPs, often categorized by their size, such as high-molecular-weight and low-molecular-weight PBPs. Specific examples include PBP1a, PBP1b, PBP2, and PBP3, each having slightly different but related roles in constructing the cell wall. While their precise functions can vary, they all contribute to the synthesis and modification of peptidoglycan.
This diversity allows the bacterium to carry out different aspects of cell wall management simultaneously, such as elongation and cell division. For instance, some PBPs are specialized for creating the septum, the partition that forms when a bacterial cell divides into two. Others are more involved in elongating the cell before division. This coordinated action ensures the cell maintains its shape and structural integrity.
The Vital Role of PBPs in Bacterial Structure
The primary function of PBPs is to build and maintain the peptidoglycan layer of the bacterial cell wall. Peptidoglycan is a mesh-like polymer that forms a protective layer around the bacterial cell membrane. This layer gives the bacterium its shape and prevents it from bursting due to osmotic pressure. Without a robust peptidoglycan wall, the cell would be vulnerable and would lyse, or break apart.
PBPs carry out the final steps of peptidoglycan assembly through two main enzymatic activities: transglycosylation and transpeptidation. Transglycosylation involves linking together long chains of sugar molecules, specifically N-acetylmuramic acid and N-acetylglucosamine, which form the backbone of the peptidoglycan structure. This process creates the long glycan strands that make up the mesh.
Following this, transpeptidation cross-links these glycan strands by forming peptide bridges between them, which gives the cell wall its strength and rigidity. PBPs known as DD-transpeptidases are responsible for creating these connections. The continuous action of PBPs in remodeling and reinforcing this peptidoglycan mesh is necessary for the bacterium to grow and divide.
PBPs as Key Targets for Antibiotics
The role of PBPs in cell wall synthesis makes them a target for a class of antibiotics known as beta-lactams, which includes penicillins and cephalosporins. The chemical structure of beta-lactam antibiotics mimics the natural substrate that PBPs bind to during the transpeptidation step. This substrate is a pair of amino acids known as D-Ala-D-Ala.
Because of this structural similarity, the antibiotic can fit into the active site of the PBP enzyme. When a beta-lactam antibiotic binds to the PBP, it forms a stable, long-lasting bond. This binding deactivates the enzyme, preventing it from performing its cross-linking function. The PBP becomes permanently inhibited, unable to contribute to the construction of the peptidoglycan layer.
Without functional PBPs, the cell cannot properly repair or build its cell wall. As the bacterium continues to grow or attempts to divide, weak spots develop in the peptidoglycan layer. The internal pressure of the cell pushes against these weak points, causing the cell membrane to rupture, a process called lysis. This leads to the death of the bacterial cell, clearing the infection.
How Bacteria Evade Antibiotics by Altering PBPs
Bacteria have developed ways to counter the effects of beta-lactam antibiotics, with alterations to the PBPs themselves being a primary strategy. One common mechanism involves genetic mutations in the genes that code for PBPs. These mutations can change the shape of the antibiotic’s binding site on the PBP enzyme. The result is a PBP that has a lower affinity for the antibiotic, which allows it to continue cell wall synthesis even when the antibiotic is present.
An example of this resistance is seen in Methicillin-resistant Staphylococcus aureus (MRSA). These bacteria have acquired a gene called mecA, which produces a new type of penicillin-binding protein known as PBP2a. PBP2a has a low affinity for most beta-lactam antibiotics, so it can continue to build the cell wall when all other native PBPs are blocked by the drug. The presence of PBP2a makes MRSA resistant to methicillin and many other related antibiotics.
Penicillin-resistant Streptococcus pneumoniae (PRSP) utilizes a similar strategy by modifying its existing PBPs to reduce antibiotic binding. This makes infections caused by such strains much more difficult to treat, often requiring alternative and more potent antibiotics. While bacteria also produce enzymes called beta-lactamases that destroy antibiotics directly, the modification or acquisition of resistant PBPs is a distinct method of survival.