CELL WALL

Cell wall

Antibiotics that disrupt the synthesis of the bacterial cell wall are known as cell wall biosynthesis inhibitors (CBIs). They are one of the most effective types of antibiotic (Sarkar et al., 2017). The cell wall is integral to the health and structure of the bacteria, to maintain it’s characteristic shape, and to prevent the cell from bursting when fluids enter the cell via osmosis. Gram positive bacteria have a thicker cell wall than Gram negative bacteria (see Figure 1).

The most important part of the cell wall is the polymer peptidoglycan. Layers of peptidoglycan are cross-linked by transpeptidase (known as a penicillin-binding protein or PBP) to create the cell wall.

Gram Positive_ Negative structure (2).pn

Figure 1. Gram positive and gram negative cell wall structures.

Beta-lactam antibiotics

Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems and monobactams) have a chemical structure called a beta-lactam ring. This structure binds to transpeptidase, which prevents the synthesis of an intact bacterial cell wall (Eckburg et al.., 2019).

Because gram positive bacteria have a high internal osmotic pressure, when the cell wall is damaged the internal pressure causes the bacterial cell to burst when surrounded by a relatively low osmotic environment (see Figure 2).

The antibiotic penicillin binding protein complex stimulates the release of autolysins that can digest the existing cell wall. Beta-lactam antibiotics are therefore considered bacteriocidal agents.

Figure 2. Beta-lactam mechanism of action.

Antibiotic resistance mechanisms

Chromosomal genes can be transferred from one bacterium to another through a process called transformation. When a bacterium containing an antibiotic resistance gene dies, it’s DNA is released into the environment. A similar bacterium in the vicinity can uptake this resistant gene, and may incorporate it into it’s own chromosomal DNA through a process called homologous transformation. If enough genes are acquired, it may transform the host DNA which codes for penicillin binding proteins, altering their structure. These altered penicillin binding proteins have a reduced affinity for beta-lactam antibiotics, therefore resulting in resistance to these agents, and they can successfully link the peptidoglycan layers of the cell wall (see Figure 3). An example of this resistance occurs in methicillin-resistant Staphylococcus aureus (MRSA) (Rice, 2012).

Figure 3. Beta-lactam antibiotic resistance through homologous transformation.

Another mechanism of resistance is the production of enzymes that can inactivate or modify beta-lactam antibiotics before they have a chance to affect the bacteria. These enzymes are called beta-lactamases. The genes that code for this resistance may be found on the host DNA, plasmids, or transposable elements; bacteria can transfer copies of plasmids to each other through a process called conjugation, which involves a channel that forms between the two bacterial cells. This allows the receiving bacteria to produce beta-lactamases. (Hall et al., 2003).

Beta-lactamase inhibitors have been developed that bind to and inhibit beta-lactamase. The most successful strategy to combat this specific form of antibiotic resistance is the combining of beta-lactams with beta-lactamase inhibitors. Carbapenems and monobactams however do not need to be combined with beta-lactamase inhibitors because their beta-lactam rings are modified enough to provide them with significant resistance to beta-lactamases (Mushtaq et al. 2010) (see Figure 4).

Figure 4. Antibacterial resistance through beta-lactamase and conjugation.

References

Eckburg PB, Lister T, Walpole S, et al. (2018) Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects. Antimicrob Agents Chemother. 63(9).

Hall BG et al. (2003) Independent Origins of Subgroup Bl+B2 and Subgroup B3 Metallo-β-Lactamases. J Mol Evol 59:133-141.

Mushtaq S, Warner M, Williams G, Critchley I, Livermore DM (2010). Activity of chequerboard combinations of ceftaroline and NXL104 versus β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 65: 1428–1432.

Rice LB (2012) Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones. Mayo Clin Proc. 87(2):198-208.

Sarkar P, Yarlagadda V, Ghosh C, Haldar J, (2017) A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics. Medchemcomm. 8(3):516-533.