Antimicrobial Agents Reaching Targets
CELLULAR PERMEABILITY BARRIER
1. For Bacterial Cytoplasmic Membranes
A biological membrane that divides the interior of all cells from the outside environment is a plasma membrane or cell membrane. Basically, biological membranes consist of lipids, proteins, and lipoproteins. The cytoplasmic membrane for water, ions, nutrients, and transport mechanisms serves as a diffusion barrier. The flow of substances in and out of cells is regulated by it. Membranes are thought to be a lipid matrix of widely dispersed globular proteins to enter into the bilayer of the lipid. The production by bacteria of antimicrobial resistance is unavoidable . Resistance even to these agents has been identified, despite attempts to develop new therapeutics that interact with new targets. A variety of antimicrobial agents can cause membrane disorganization. It is possible to separate these agents into cationic, anionic, and neutral agents.
Polymyxin B and colistemethate (polymyxin E) are the best-known compounds.
How do Polymyxins Work?
- Gram-negative bacteria that have negatively charged lipids on the surface are hindered by these high-molecular-weight octapeptides.
- Since Mg2 + and Ca2 + are antagonized by the action of the polymyxins, they presumably displace Mg2 + or Ca2 + from the negatively charged phosphate groups on membrane lipids competitively.
- Polymyxins effectively disorganize the permeability of the membrane such that nucleic acids and cations spill out and the cell dies.
- As systemic agents, polymyxins are of practically no benefit as they bind to multiple ligands in body tissues and are active contaminants for the kidney and nervous system.
- Gramicidins are also antibiotics that are membrane-active and tend to act by forming aqueous pores in the membranes.
For Gram Negative Bacteria
The tolerance of Gram negative bacteria to a significant number of noxious agents is because of the consequence of effective permeability of their outer membrane barrier. It is impermeable to macromolecules and only makes small diffusion by the lipopolysaccharide (LPS)-covered surface to hydrophobic compounds. The outer leaflet of the manuscript Glycerophospholipids are deficient in enterobacterial outer membrane and, hence are efficient hydrophobic diffusion channels. The outer membrane of these bacteria is also immune to detergents that are neutral and anionic. Via the water-filled porin pores, minor hydrophilic compounds disperse through the outer membrane, but the narrowness of these networks greatly limits their dissemination. Since many of the damaging agents are either hydrophobic or comparatively large hydrophilic compounds, like antibiotics, they penetrate the outer membrane poorly. In addition, the polysaccharide components of the OM help bacteria prevent phagocytosis and shield the deeper parts of the OM from binding to the complement and antibody.
Fungal membranes contain sterols. A rigid hydrophobic core and a flexible hydrophilic portion are included in the polyene antibiotics that apparently act by binding to membrane sterols.
How Polyenes work?
- Polyenes are structurally closely packed rods retained by the polyene part in the rigid expansion.
- In order to create a membrane-polyene complex that changes the permeability of the membrane, they interact with fungal cells, resulting in internal acidification of the fungus with the exchange of K+ and sugars; depletion of phosphate esters, amino acids, nucleotides; and subsequent cell protein leakage.
- In effect, in the fungal membrane, the polyene creates a pore and leaks out the contents of the fungus. Prokaryotic cells do not bind to polyenes or are blocked by them. While several polyene antibiotics have been isolated, systematic use is only of amphotericin B