Question

1. Why is peptidoglycan synthesis so important for bacteria (and humans)? Describe the major steps in peptidoglycan synthesis and note which steps can be targeted by antibiotics.

2. What are the characteristics of an effective antibiotic drug?

Answer 1

• Why is peptidoglycan synthesis so important for bacteria :-

The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm.

• Describe the major steps in peptidoglycan synthesis and note which steps can be targeted by antibiotics :-

The peptidoglycan monomers are synthesized in the cytosol and are then attached to a membrane carrier bactoprenol. Bactoprenol transports peptidoglycan monomers across the cell membrane where they are inserted into the existing peptidoglycan.

In the first step of peptidoglycan synthesis, glutamine, which is an amino acid, donates an amino group to a sugar, fructose 6-phosphate. This turns fructose 6-phosphate into glucosamine-6-phosphate. In step two, an acetyl group is transferred from acetyl CoA to the amino group on the glucosamine-6-phosphate creating N-acetyl-glucosamine-6-phosphate. In step three of the synthesis process, the N-acetyl-glucosamine-6-phosphate is isomerized, which will change N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate.

In step 4, the N-acetyl-glucosamine-1-phosphate, which is now a monophosphate, attacks UTP. Uridine triphosphate, which is a pyrimidine nucleotide, has the ability to act as an energy source. In this particular reaction, after the monophosphate has attacked the UTP, an inorganic pyrophosphate is given off and is replaced by the monophosphate, creating UDP-N-acetylglucosamine (2,4). (When UDP is used as an energy source, it gives off an inorganic phosphate.) This initial stage, is used to create the precursor for the NAG in peptidoglycan.

In step 5, some of the UDP-N-acetylglucosamine (UDP-GlcNAc) is converted to UDP-MurNAc (UDP-N-acetylmuramic acid) by the addition of a lactyl group to the glucosamine. Also in this reaction, the C3 hydroxyl group will remove a phosphate from the alpha carbon of phosphoenolpyruvate. This creates what is called an enol derivative that will be reduced to a “lactyl moiety” by NADPH in step six.

In step 7, the UDP–MurNAc is converted to UDP-MurNAc pentapeptide by the addition of five amino acids, usually including the dipeptide D-alanyl-D-alanine. Each of these reactions requires the energy source ATP.This is all referred to as Stage one.

Stage two occurs in the cytoplasmic membrane. It is in the membrane where a lipid carrier called bactoprenol carries peptidoglycan precursors through the cell membrane. Bactoprenol will attack the UDP-MurNAc penta, creating a PP-MurNac penta, which is now a lipid. UDP-GlcNAc is then transported to MurNAc, creating Lipid-PP-MurNAc penta-GlcNAc, a disaccharide, also a precursor to peptidoglycan. How this molecule is transported through the membrane is still not understood. However, once it is there, it is added to the growing glycan chain.The next reaction is known as tranglycosylation. In the reaction, the hydroxyl group of the GlcNAc will attach to the MurNAc in the glycan, which will displace the lipid-PP from the glycan chain. The enzyme responsible for this is transglycosylase.

• What are the characteristics of an effective antibiotic drug :-

An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host.

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