Antimicrobial mechanism of action

Introduction

Clinically potent antibacterial drugs are distinguished from antiseptics by their selective toxicity toward the microorganism rather than the host. In most instances, selectivity is defined by action on microbial metabolism or microbial cellular structures that differ from those of mammalian cells. Some drugs, for example, act on the synthesis of bacterial cell walls (cell wall is not present in eukaryotes), whereas others work on the bacterial ribosome of 70s but not the eukaryotic ribosome of 80s types. Some antimicrobials, such as penicillin, are generally safe to the host until hypersensitivity develops. For some, such as aminoglycosides, the ideal therapeutic dose is very close to the lethal dose, that would even require dosage adjustment and even blood pressure monitoring.

Antibacterial agents

Clinically, there are around 23 distinct classes and 18 subclasses of clinically antibacterial drugs, for a total of approximately 100 antibiotics. The classification system of antibiotics are complex, since they are continuously evolving as new classes emerge or existing classes are optimized. Their mechanism of action include different targets like, bacterial cell wall synthesis, folate synthesis, DNA replication, RNA transcription, and mRNA translation. The metabolic processes for bacterial survival are distinct enough from the eukaryotic cells allowing for selective toxicity. Understanding the mechanisms of antibiotic action, on the other hand, provides insight into the strategies used by microorganisms to evade their harmful effects.

An effective antimicrobial agent features selective toxicity, which means it may be destructive to bacteria thereby not affecting the host. Selective toxicity can occur as a result of suppressing metabolic activities important to the pathogen but not the host. Antimicrobial medication mechanisms of action are classified into four categories:

1. Inhibition of cell wall synthesis
2. Inhibition of cell membrane function
3. Inhibition of protein synthesis
4. Inhibition of nucleic acid synthesis

Inhibition of cell wall synthesis

Most antibacterial drugs work by controlling bacterial cell wall synthesis. Cell walls do not exist in mammalian cells, and the composition of cell also does varies among bacterial species. Cell wall synthesis provides possibility of potential treatments for bacterial infections.

A chemically distinct complex polymer “mucopeptide” (“peptidoglycan”) consisting of polysaccharides and a polypeptide with strong cross-linkage comprises the cell wall. Regularly, polysaccharides include the amino sugars N-acetylglucosamine and acetylmuramic acid. The amino sugars are attached to little peptide chains. The ultimate rigidity of the cell wall is provided by cross-linking the peptide chains (for example, by pentaglycine bonds) as a consequence of the several enzyme transpeptide reactions. The peptidoglycan layer in the gram-positive cell wall is substantially thicker than that in the gram-negative cell wall.

The most often utilized include cell wall biosynthesis inhibitors, β-lactams, and glycopeptides. Penicillin-binding proteins (PBPs), which are catylyst transpeptidase-transglycosylase enzymes that mediate peptidoglycan cross-linking, are bound by β-lactam antibiotics such as penems, cephems, carbapenems, and monobactams.

Inhibition of cell membrane function

The cytoplasms of all living cells are confined by the cytoplasmic membrane, which acts as a selective barrier to permeability and executes active transport functions, thereby regulating the cell’s internal metabolism. When the cytoplasmic membrane’s functional stability is disrupted, macromolecules and ions escape from the cell, causing cell damage or death. The cytoplasmic membrane of bacteria and fungus differs from that of animal cells and is more easily destroyed by external chemicals. . Polymyxins are detergent-like cyclic peptides that electively degrade phosphatidylethanolamine-containing membranes which are a prominent component of bacterial membranes.

Daptomycin is a newer lipopeptide antibiotic that is effectively bactericidal that ion-dependent on the cell membrane and thereby depolarizes bacterial membrane potential. This leads to the generation of potassium intracellularly. This antibiotic is now used for the treatment of S. aureus bloodstream infections as well as skin and soft tissue infections caused by gram-positive bacteria, particularly those resistant to β-lactam medicines and vancomycin. Amphotericin B, colistin, imidazoles and triazoles are some examples of drugs that function by disrupting cell membrane integrity.

Inhibition of protein synthesis

Protein synthesis in bacteria can be inhibited by Macrolides, Lincosamides, Tetracyclines, Glycylcyclines, Aminoglycosides, and Chloramphenicol. Different antibiotics have different mechanism of action.

Bacterial cells have 70s ribosomes, but mammalian cells have 80s ribosomes. The subunits of a ribosome type, as well as its chemical makeup and functional capabilities, differ significantly to explain why antimicrobial agents may limit protein synthesis in bacterial ribosomes while having no effect on mammalian ribosomes.

Aminoglycosides are potent in a broad spectrum of bacteria, but only in those that can transport them into cells via an oxidative phosphorylation pathway. Streptomycin, the initial aminoglycoside, is related with the 30s ribosomal subunit, whereas the newer and more active aminoglycosides are associated with both the 30s and 50s subunits.

Tetracyclines bind to the 30S ribosome subunit and prevent amino-acyl-tRNA from attaching to the acceptor site on the mRNA ribosome complex. In contrast to aminoglycosides, they are bacterial growth inhibitors (bacteriostatic) rather than bactericidal.

Chemical synthesis can be used to mass produce the Chloramphenicol ring’s nitrobenzene structure. The consequence of this action is to attach to the 50s ribosomal subunit and inhibit peptidyl transferase activity, thereby preventing peptide bonds that are required for peptide chain expansion. These actions are also bacteriostatic.

The macrolides erythromycin, azithromycin, and clarithromycin all have a macrocyclic lactone ring structure with 14 or 15 members. They have an effect on ribosomal protein production by binding to 50s subunit and inhibiting the translocation process. They mostly have a bacteriostatic effect.

Inhibition of nucleic acid synthesis

Quinolones, pyrimethamine, rifampin, sulfonamides, trimethoprim, and trimetrexate are examples of drugs that function by inhibiting nucleic acid synthesis.

Quinolones target DNA gyrase and topoisomerase IV enzymes responsible for supercoiling, and protecting bacterial DNA during replication. Quinolones like levofloxacin and ciprofloxacin are primarily passed through the kidney, and they have higher concentrations in the urine, making them useful for the treating of several urinary tract infections.

Sulfonamides are structural analogs of PABA and compete with it for the enzyme (dihydropteroate synthetase), which incorporates PABA and pteridin in the first stage of folate production. The most major consequence of this inhibition on bacterial cells is the obstruction of nucleic acid synthesis.

Trimethoprim acts on the folate production pathway, but after sulfonamides. It inhibits the action of the bacterial dihydrofolate reductase, which catalyzes the conversion of folate to its reduced active coenzyme form. Trimethoprim, when coupled with sulfamethoxazole, a sulfonamide, contributes to the disruption of the folate pathway in two phases, typically resulting in synergistic bacteriostatic or bactericidal activity.

Rifampin binds to the β-subunit of DNA-dependent RNA polymerase, preventing the bacterial DNA-dependent RNA synthesis. This antibiotic is primarily used to treat TB and leprosy, and it also sometimes used in the prevention of methicillin-resistant Staphylococcus aureus (MRSA). Enterobacteriaceae, acinetobacter, and pseudomonas species, on the other hand, are intrinsically resistant to rifampicin.

Antibiotic Targets and Pathways

References:

1. Textbook of Diagnostic Microbiology 5^th Edition. Saunders Elsevier
2. Jawetz, Melnick and Adelberg’s Medical Microbiology 26^th Edition
3. Sherris Medical Microbiology 6^th Edition
4. Bailey and Scott’s Diagnostic Microbiology 13^th Edition