2.6. Pore forming toxins (PFT’S)
Some bacteria like Clostridium septicum and Staphylococcus aureus produce proteotoxins that makes numerous unregulated pores in the membrane of the targeted cells to kill them.
These pore forming toxins are classified into the sub categories as shown in the given table:
β–Pore forming toxins are dimorphic proteins mostly made up of β–strands based domains that are soluble monomers and assemble to form the pore. Such pore disrupts the regulated gradient of ions and small molecules of cytoplasm and allowing continues outflow along with nucleotides and amino acids. They also facilitate the excess diffusion of water into the cell that leads to blebbing (swelling) and finally to the cell death because of burst.
Binary toxins consists of, component A (an enzymatic component) and component B (a membrane altering component). The component B forms homo oligomeric pores that facilitate the entry of component A to the cytosol where it inhibits the following normal cell processes.
- Polymerisation of G-actin to F-actin by mono ADP-ribosylation at arginine 177 of G-actin leading to cell death.
- Zinc-metalloprotease of component A interferes with the MAPKK signalling and making the cell insensitive to extracellular stimuli.
- Increase the Ca+2 influx and rises the intracellular cAMP levels that blocks the leukocyte proliferation, phagocytosis and release of porin inflammatory cytokines.
These are the hydrophobic molecules produced by microorganisms that facilitate the ion transport across the lipid bilayer of the cell membrane. There are two categories of ionophores are
- Carriers compounds: These are the mobile ion carriers that facilitates the transport of ions through the lipid membranes by masking their charge.
- Channel formers: These ionophores make a hydrophilic pore in the lipid bilayer that allows the ion transport by avoiding their contact with lipid bilayer.
These molecules simply works as an antibiotics and disrupts the ion gradient that is necessary for normal cell functioning. This is a potent act of defence among microbes with their competitors. Many ionophores shows very strong affinities for Na+ and K+ like macrolides.
2.7.1. Ionophores for Ca+2
A23187 (calcimysin) : This antibiotic is produced during fermentation by Streptomyces. It acts as ionophores for divalent cations like Ca+2, Mn+2, Ba+2, Mg+2, Sr+2. It also uncouples of mitochondrial ATP synthesis activity and used in In Vitro Fertilization (IVF) as a potent Ca+2 ionophores.
Beauvericin: It is the depsipeptide isolated from fungus Beauveria bassiana. It is also produced by other fungus having antibiotic and insecticide effects. It acts as an ionophore for alkali metal ions.
Ionomycin is also a Ca+2 ionophore used to increase the inner Ca+2 levels for the production of cytokines like interferon, perforin, IL-2, and IL-4 that has a significant inflammatory response. These are produced by a bacterium, Streptomyces conglobatus.
2.7.2. Ionophores for Na+
Monensin A is an ionophore for monovalent cations like Li+, Na+, K+, Ag+ and also has crucial role as an Na+/H+ antiporter. It exhibits antibiotic, antimalarial and inhibits protein transport. It is a polyether isolated from Streptomyces cinnamonensis.
Gramicidin A is also a monovalent (Na+ & K+) ionophore obtained from the soil bacterial species Bacillus brevis, used to induce hemolysis in lower concentrations than bacteria cell death. It is active against Gram positive and some Gram negative bacteria.
2.7.3. Ionophores for K+
Valinomycin is natural neutral ionophore obtained from Streptomyces tsusimaensis and Streptomyces fulvissimus. It is a dodecadepsipeptide highly selective for K+ ion over Na+ within the membrane. The value of stability constant K with these ions are 106 and 10 respectively. It consists twelve alternate amino acid residues and esters that creates its affinity for metal ions and responsible for salvation in polar solvents. Recently Valinomycin is suggested as a potent agent against SARS corona virus, which is responsible for severe acute respiratory syndromes.
Nigericin is also a monensin like antibiotic produced by Streptomyces hygroscopicus but commercially it is obtained during fermentation of geldanamycin, as a byproduct. It is also named as Antibiotic K178/X-464, Helixin C, Azalomycin M or Polyetherin A. Both salinomycin and gramicidin are the antibiotics that also work as K+ ionophores.