Brief Review about Antibiotics and Cell Wall

Antibiotic is a kind of drug that kills bacteria. Since penicillin was discovered by Alexander Fleming, human beings got able to cure bacterial disease(including getting infected) more easily. However, due to abuse and over using it, it caused emergence of antibiotic resistant bacteria like MRSA(methicilline resistant Staphylococcus aureus). Anyway, at this writing, I’m going to discuss about 1) what kind of antibiotics exist 2) and how they work.

 

Before we get started, we need to know what kind of difference exists between Gram-positive bacteria and Gram-negative bacteria. Gram-positive bacteria have simple but thick cell wall, by the way, Gram-negative bacteria have complicated cell wall. Also, Gram-positive bacteria have one phospholipid bilayer, however, Gram-negative bacteria have two phospholipid bilayer with the complicated cell wall between them. These are the main difference between two kind of bacteria and according to this, how to kill them gets different. This is just simple information about Gram-positive and negative bacteria and I guess I need to learn more about them by studying cell biology and molecular biology.

These are just simple diagram to compare what the difference is between Gram-positive and negative.

 

Anyway, what kind of antibiotics exist and what do they target to kill bacteria? There are antibiotics targeting the bacterial ribosome, DNA gyrase and tetrahydrofolic acid(it’s a very important thing needed for the survival of living organisms) and inhibiting the cell wall synthesis(e.g. drugs with β-lactam ring). So what I am going to focus on is drugs that inhibits cell wall synthesis. Well then, how does it made? Cell wall is made of peptidoglycan which is composed of a repeating carbohydrate backbone subunit(NAM-NAG; these backbones are cross linked by short peptides). So how is it formed? First, carbohydrate(NAM-NAG) subunits are activated by attachment to a carrier molecule called UDP(nucleotide uridine diphosphate). And then peptide linkage is synthesized. The pentapeptide is added to UDP-NAM with the 2 terminal alanine residues added as a dipeptide. There is something interesting with this peptide. There are some non-standard amino acids like DAP, diaminopimelic acid, which is metabolic precursor of lysine. These sequence is not encoded in DNA, but formed due to the specificity of the enzymes that form the peptide bonds. After this process, the peptidoglycan unit is transferred to bactoprenol phosphate(BPP). The NAM-PEP moiety is transferred from the UDP carrier to BPP, which is another carrier. At this point, NAG of UDP-NAG is transferred to NAM-PEP and the repeating unit of the peptidoglycan is completed forming NAG-NAM-PEP-BPP. Well then, the repeat unit is added to the existing peptidoglycan forming the cell wall. NAG-NAM-PEP repeat unit is carried out to the outside of the cell membrane where the previous peptidoglycan group exists. Free ends of the preexisting peptidoglycans are created by limited hydrolytic loosening. After all of these, pentapeptide is cross linked to the peptidoglycan backbone. N-terminal end of the pentapeptide is attached to the NAM-moieties of the backbone and C-terminal is dangling free. How they get along together leads to cross linkage. By a transpeptidation reaction, DAP and D-alanine – D-alanine becomes L-lysine – D-alanine, which means DAP and D-alanine is changed into L-lysine. Cell wall of Gram-positive bacteria is connected indirectly. There is a glycine bridge which connects L-lysines at each peptides. However, cell wall of Gram-negative is connected directly. There are pictures that explain about this process right below. I think there would be more information about it and may be I am going to search more about it!

This is a picture from Microbiology ( Lippincott's Illustrated Reviews) -1

This is a picture from Microbiology ( Lippincott's Illustrated Reviews) -2

Antibacterial agents that target peptidoglycan biosynthesis are β-lactam antibiotics, bacitracin and vancomycin. There are penicillins, cephalosporins and e.t.c. for β-lactam antibiotics which inhibit enzymes for transpeptidation and carboxypeptidation reaction of cell wall assembly. There are PBPs(penicillin-binding proteins) at the components that form a cell wall and β-lactam antibiotics binds to PBPs. However, due to the over use and abuse of this kind of drugs, a lot of bacteria acquired resistance to it. Bacitracin inhibits the recycling of bactoprenol phosphate; cycloserine and this leads to inhibition of the D-ala – D-ala dipeptide which provides the 2 terminal residues of the pentapeptide. Vancomycin is one of the most strongest antibiotics. It blocks incorporation of the NAM-NAG-PEP repeat unit into the growing peptidoglycan chain. It also blocks D-ala – D-ala dipeptide which leads to prevention of transpeptidation.

 

After studying about cell wall and antibiotics, I felt that there could be some phytochemical that can inhibit the growth of bacteria. But to do this, I need to study more about physiological characteristics of bacteria and plants and their phytochemical with antimicrobial activity.