ß-Lactams: Mechanisms of Action and Resistance

structurally most bacteria consist of a cell membrane surrounded by a cell wall and for some bacteria an additional outer layer internal to the cell membrane is the cytoplasm which contains ribosomes a nuclear region and in some cases granules and/or vesicles depending on the bacterial species a number of different external structures may be found such as a capsule flagella and pillai in gram-negative bacteria the gap between the cell membrane and the cell wall is known as the periplasmic space most gram positive bacteria do not possess a periplasmic space but have only periplasm where metabolic digestion occurs

and new cell peptidoglycan is attached peptidoglycan the most important component of the cell wall is a polymer made of an acetone Meramec acid alternating with n acetyl glucosamine which are cross-linked by chains of four amino acids the function of the bacterial cell wall is to maintain the characteristic shape of the organism and to prevent the bacterium from bursting when fluid flows into the organism by osmosis synthesis of the peptidoglycan and ultimately the bacterial cell wall occurs in a number of stages one of the first stages is the addition of five amino acids to n-acetylmuramic acid

next an acetone glucosamine is added to the n-acetylmuramic acid to form a precursor of peptidoglycan this peptidoglycan precursor is then transported across the cell membrane to a cell wall acceptor in the periplasm once in the periplasm the peptidoglycan precursors bind to cell wall acceptors and undergo extensive cross-linking two major enzymes are involved in cross-linking transpeptidase and d al Anil carboxy peptidase these enzymes are also known as penicillin binding proteins because of their ability to bind to penicillin and cephalosporins eventually several layers of peptidoglycan are formed all of which are cross linked to create the cell

wall gram positive bacteria may have more layers than gram-negative bacteria and thus have a much thicker cell wall beta-lactam antibiotics include all penicillins and cephalosporins that contain a chemical structure called a beta lactam ring this structure is capable of binding to the enzymes that cross-linked peptidoglycan beta lactams interfere with cross-linking by binding to transpeptidase and d al Anil carboxy peptidase enzymes thus preventing bacterial cell wall synthesis by inhibiting cell wall synthesis the bacterial cell is damaged gram-positive bacteria have a high internal osmotic pressure without a normal rigid cell wall these cells burst when subjected to

the low osmotic pressure of their surrounding environment as well the antibiotic penicillin binding protein complex stimulates the release of auto license that are capable of digesting the existing cell wall beta-lactam antibiotics are therefore considered bacterial SCYTL agents bacterial resistance to beta-lactam antibiotics may be acquired by several routes one of the most important mechanisms is through a process known as transformation during transformation chromosomal genes are transferred from one bacterium to another when a bacterium containing a resistance gene dies naked DNA is released into the surrounding environment if a bacterium of sufficient similarity to the dead one

is in the vicinity it will be able to uptake the naked DNA containing the resistance gene once inside the bacterium the resistance gene may be transferred from the naked DNA to the chromosome of the host bacteria by a process known as homologous transformation over time the bacterium may acquire enough of these resistance genes to result in remodeling of the segment of the host DNA if this remodeled DNA segment codes for cross-linking enzymes ie penicillin binding proteins the result is the production of altered penicillin binding proteins these altered penicillin binding proteins can still cross link the

peptidoglycan layers of the cell wall but have a reduced affinity for beta-lactam antibiotics thus rendering the bacterium resistant to the effects of penicillin and other beta lactam agents this transfer process has resulted in penicillin resistant s pneumonia through the acquisition of genes from other naturally-occurring penicillin resistant streptococcus species a second important mechanism by which bacteria become resistant to beta-lactam antibiotics is by the production of enzymes capable of in activating or modifying the drug before it has a chance to exert its effect on the bacteria depending on the bacterial species the gene coding for these enzymes

may be found as part of the host DNA or on plasmids which are small self-replicating units of genetic material bacteria are capable of passing these resistance plasmids to each other by conjugation when two bacteria come into close contact with each other a small channel is created between them which allows one of the bacteria to pass a copy of the resistance plasmid to the other if the plasmid is transcribed and translated the bacteria will begin to produce in activating enzymes these enzymes capable of destroying beta-lactam antibiotics are known as beta lactam Aizaz in gram positive bacteria

the beta lactamase enzyme is generally inducible resulting in a large amount of enzyme being produced in the presence of the drug in gram-negative bacteria the beta lactam enzymes are produced constitutively ie even when the antibiotic is not present gram positive bacteria released the beta-lactamase enzyme from the cell into the extracellular environment where it inactivates the drug before it enters the bacterial cell in contrast gram-negative bacteria retain the beta lactamase enzyme within the periplasmic space resulting in a more efficient mechanism than gram positive bacteria ultimately the destruction of the beta-lactam ring of the antibiotic renders it

incapable of binding to the penicillin binding protein and thus the bacteria become resistant to that drug or class of drugs