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10 months ago
Oct 12, 2021


ANTIBIOTICS - CELL MEMBRANE INTEGRITY DISRUPTORS

ANTIBIOTICS_-CELL_MEMBRANE_INTEGRITY_DISRUPTORS
The selection of antibiotics depends largely on the clinical manifestation of the infection and the patient profile. Culture sensitivity results often guide it. The Kirby-Bauer method is one of the most commonly performed tests that help to guide the selection of an eff

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Antibiotics are broadly defined as chemical agents that kill or inhibit the growth of microorganisms. It may be classified as broad-spectrum, meaning they act against a wide range of microorganisms, or narrow-spectrum, meaning they act against very few types of microorganisms.

Antibiotics may be categorized as bactericidal, meaning they kill bacteria, or bacteriostatic, meaning they only stop bacteria from growing.

The selection of antibiotics depends largely on the clinical manifestation of the infection and the patient profile. Culture sensitivity results often guide it. The Kirby-Bauer method is one of the most commonly performed tests that help to guide the selection of an effective antibiotic.

In contrast, the dilution test is commonly performed to determine the lowest antibiotic concentration that inhibits visible bacterial growth, known as minimum inhibitory concentration or MIC. And the lowest concentration of antibiotics that kills at least 99.9% of bacteria is the minimum bactericidal concentration or MBC.

How Antibiotics Works

Based on their action mechanism, antibiotics can be divided into five broad categories

  1. cell wall synthesis inhibitors
  2. cell membrane integrity disruptors
  3. nucleic acid synthesis inhibitors
  4. protein synthesis inhibitors
  5. five metabolic pathway inhibitors

CELL WALL SYNTHESIS INHIBITORS

The cell wall has vital importance for the survival and growth of bacteria. It gives the bacterial cell its shape and protects it against spontaneous cell lysis due to the high internal osmotic pressure that results from a high concentration of proteins within the bacterial cytoplasm. The vast majority of bacteria have one of two different types of cell walls. The first one is called gram-negative, and it is composed of the outer membrane linked by lipoproteins to a thin inner layer of peptidoglycan.

The second one is called gram-positive. It is composed of many interconnected layers of peptidoglycan. And it lacks the outer membrane. Now peptidoglycan is what gives both cell wall types their rigid and protective qualities. It consists of glycan chains of alternating N-acetylglucosamine NAG for short and n-acetylmuramic acid NAM with a short peptide chain attached to it.

The biosynthesis of peptidoglycan is mediated by transpeptidase enzymes, also known as penicillin-binding proteins. Specifically, penicillin-binding proteins catalyze the final transpeptidation reaction that results in the formation of a bond between the last lysine residue of one peptidoglycan and the terminal alanine on the other strand.

For bacteria to grow and divide, a new cell wall must be continuously built this way. So this is where inhibitors of cell wall synthesis come into play. Most of the antibiotics belonging to this group are characterized by beta-lactam ring at the core of their structure, which resembles substrates for penicillin-binding protein.

When the penicillin-binding protein binds to the beta-lactam ring portion of the drug, covalent bonds are formed, resulting in a permanently blocked active site. This makes the enzyme unable to perform its role in cell wall synthesis, leading to bacteria’s death due to osmotic instability or autolysis.

 

The beta-lactam ring is part of several antibiotic families’ structures, namely penicillins, cephalosporins, carbapenems, and monobactams. We call them beta-lactam antibiotics. Due to the large number of antibiotics that belonged to this family, keep in mind that this diagram is not meant to be detailed. All looks good up to this point.

We have all these powerful antibiotics that can easily kill all harmful bacteria. Over the years, exposure to antibiotics provided bacteria with selective pressures, leading to different resistance mechanisms.

The most common mechanism for drug resistance to beta-lactam antibiotics is a bacterial synthesis of beta-lactamases. Beta-lactamases are enzymes produced by certain types of bacteria that break the beta-lactam ring and destroy antibacterial activity. To fight back against this resistance, scientists could develop beta-lactamase inhibitors that irreversibly bind to and inhibit beta-lactamase enzymes.

The use of beta-lactamase inhibitors, in combination with beta-lactam antibiotics, is currently the most successful strategy that we have to combat this specific mechanism of resistance. However, there are exceptions here, carbapenems and monobactams.

Unlike penicillins and cephalosporins, they don’t need to be combined with beta-lactamase inhibitors. They have modified beta-lactam rings in their structures that provide them with significant resistance to beta-lactamases. Examples of beta-lactamase inhibitors are avibactam, clavulanic, acid sulbactam, and tazobactam.

Side-Effects Of Beta-Lactam Antibiotics

 All beta-lactam antibiotics are likely to cause nausea, vomiting, and diarrhea, in addition to a small number of patients may experience allergic reactions ranging from mild rashes to life-threatening anaphylaxis.

Beta-lactams are not the only antibiotics that interfere with the synthesis of the bacterial cell wall. Fosfomycin, cycloserine, vancomycin, and bacitracin also disrupt cell wall synthesis. However, they accomplish that through a different mechanism. In order to acquire a deeper understanding of how these antibiotics work, first, we need to take a closer look at the enzymatic steps involved in cell wall synthesis.

The first major step of the cell wall synthesis involves the cytoplasmic enzyme enolpyruvate transferase, abbreviated as MurA. MurA catalyzes the addition of phosphoenolpyruvate, abbreviated PEP to UDP-n-acetyl-glucosamine to form UDP-n-acetyl-muramic acid, to which then three amino acids are sequentially added.

The next crucial step involves two enzymes, the first, d-alanine racemase that converts l-alanine into d-alanine, and the second d-alanine:d-alanine ligase that joins to d-alanine molecules, which are then incorporated into the growing peptidoglycan precursor. Next, with the help of the translocase enzyme, peptidoglycan precursor is transferred to the lipid carrier, called undecaprenyl-pyrophosphate, also known as bactoprenol. This is followed by the sequential addition of N-acetylglucosamine along with five amino acid molecules.

Once this cell wall building block is transported across the inner membrane, penicillin-binding proteins catalyze the final step of polymerization of n-acetylmuramic acid and N-acetylglucosamine complexes via transglycosylation and cross-linking of chains via transpeptidation. The bactoprenol lipid carrier gets dephosphorylated at the end, which enables it to perform another round of transfer.

Let’s examine how four antibiotics disrupt cell wall synthesis machinery.

1. Fosfomycin

Fosfomycin acts in the first cytoplasmic step of the cell wall synthesis by irreversibly inhibiting the MurA enzyme. This, in turn, prevents the peptidoglycan precursor’s formation and eventually leads to bacterial cell death.

2. Cycloserine

Second antibiotic cycloserine, comes into play at the next crucial step of the synthesis. Because of its chemical resemblance to d-alanine, cycloserine competitively inhibits both d-alanine racemase and d-alanine:d-alanine ligase. When any of these enzymes are blocked, it is difficult to form d-alanine residues, and previously formed molecules of d-alanine can not be joined together. Again the formation of peptidoglycan precursor is disrupted, which eventually leads to the death of bacteria.

3. Vancomycin

Vancomycin belongs to a small family of antibiotics called glycopeptides that includes few other drugs that work in a similar way. So unlike fosfomycin and cycloserine, vancomycin works in the late stages of cell wall synthesis.

Specifically, vancomycin interferes with transpeptidation and transglycosylation during peptidoglycan assembly by binding to two d-alanine residues at the top of the peptide chains. This binding prevents the linking of long polymers of n-acetylmuramic acid and n-acetylglucosamine that form the peptidoglycan backbone. And it prevents cross-linking between amino acid residues in the peptidoglycan chain. Again this brings cell construction to a halt, which ultimately results in bacterial cell death.

4. Bacitracin

Our last antibiotic, bacitracin, which comes into play at the end of the synthetic process. Bacitracin works by binding to bactoprenol after it inserts the peptidoglycan into the growing cell wall. This prevents the dephosphorylation of the transport protein, making it unable to regenerate and perform its job in constructing the cell wall.

Side-Effects

Fosfomycin is most likely to cause nausea, headaches, dizziness, and diarrhea. Neurologic and psychiatric disturbances such as peripheral neuropathy, psychosis, and depression have been associated with cycloserine.

Vancomycin may cause hypotension and flushing of the upper body condition, known as redman syndrome when given intravenously. Vancomycin can also cause ototoxicity, nephrotoxicity, and blood disorders, including neutropenia, in rare instances.

Bacitracin rarely causes side-effects other than minor skin irritation when used topically. However, nausea, vomiting, allergic reactions, and nephrotoxicity may occur when administered intravenously. So, in species of gram-positive or gram-negative bacteria or both, the antibiotics we discussed here are typically capable of disrupting cell wall synthesis. However, our antibiotic arsenal, the mycobacterial cell wall, presents a significant challenge to one more bacterial cell type.

Mycobacteria are highly pathogenic organisms that are responsible for tuberculosis and leprosy, which are deadly diseases. Moreover, for their ability to resist most antibiotics, mycobacteria are notorious. Their exceptionally impermeable cell wall is one of the main reasons for their strength. Five major components linked together make up the mycobacterial cell wall.

The inner plasma membrane, a thin layer of peptidoglycan and arabinogalactan, is surrounded by a thick layer of mycolic acid and an outer membrane-containing lipid. For the survival of mycobacteria, this cell wall is essential. Several antibiotics have been developed to disrupt its integrity. Well-known antituberculosis drugs, isoniazid and ethambutol, are the two agents thought to primarily target mycobacterial cell wall synthesis.

The Primary Action Mechanism

The first one, isoniazid, is a prodrug that must first be activated by a bacterial catalase-peroxidase enzyme called KatG upon entry into the cell. Isoniazid forms an adduct once activated in NADH, which then binds to the enoyl-acyl carrier protein reductase abbreviated as InhA and thereby inhibits it.

InhA is a type 2 fatty acid system that synthesizes mycolic acid by elongating long-chain fatty acids. Mycolic acid synthesis inhibition, in turn, leads to a loss of structural integrity and physiological function of the cell that ultimately results in the death of bacterial cells.

Inhibition of the membrane-associate enzyme called arabinosyl transferase EmbB appears to be the primary mode of action of ethambutol. This enzyme mediates arabinose polymerization, an essential component of the mycobacterial cell wall, into arabinogalactan.

The permeability of the cell wall increases due to this enzyme inhibition, enabling toxic substances to enter the cell. Isoniazid can cause hepatotoxicity and peripheral neuropathy when it comes to major side effects. Ethambutol optic neuritis can lead to vision loss.

RESOURCE



Anastasiya Meintjes

Oca 18, 2021

Very useful information, put together in an informative structure.

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