Polymyxin B is a type of antibiotic used to treat severe bacterial infections. It belongs to a class of compounds called polymyxins, which were discovered in 1947. These antibiotics are naturally produced by certain Gram-positive bacteria. Polymyxin B has a distinct structure as a cyclic lipodecapeptide, meaning it has a circular chain of amino acids with an attached fatty acid tail.
How Polymyxin B Disrupts Bacteria
Polymyxin B primarily acts by targeting the outer membrane of Gram-negative bacteria, which is a unique structural feature of these microorganisms. The antibiotic, being positively charged, is strongly attracted to the negatively charged lipopolysaccharide (LPS) molecules found in the outer leaflet of this membrane. This electrostatic attraction allows polymyxin B to bind to the lipid A portion of LPS, a key component of the outer membrane.
Once bound, polymyxin B displaces divalent cations like magnesium (Mg²⁺) and calcium (Ca²⁺) that normally stabilize the LPS layer. This displacement disrupts the structural integrity of the outer membrane, making it more permeable. The hydrophobic tail of polymyxin B then causes further membrane damage, suggesting a detergent-like action.
The disruption of the outer membrane allows polymyxin B to cross into the periplasmic space, the area between the outer and inner membranes of Gram-negative bacteria. From there, it can interact with the inner or cytoplasmic membrane, which is responsible for maintaining the cell’s internal environment and energy production. This interaction further increases membrane permeability, leading to the leakage of essential cellular contents, such as ions, nucleotides, and proteins, from the bacterium. This uncontrolled leakage ultimately causes the bacterial cell to die.
Specific Bacterial Targets
Polymyxin B is particularly effective against Gram-negative bacteria due to its specific interaction with their outer membrane. Gram-positive bacteria, which lack this outer membrane and have a thick peptidoglycan layer, are generally unaffected by Polymyxin B.
This antibiotic is used against a range of multidrug-resistant Gram-negative pathogens. Examples include Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. It is also effective against other Enterobacteriaceae. However, polymyxin B is not effective against Gram-negative cocci or anaerobic bacteria.
When Polymyxin B is Used
Polymyxin B is often considered a “last resort” antibiotic when other commonly used antibiotics have failed to eradicate the infection. This includes serious infections such as ventilator-associated pneumonia, bloodstream infections, intra-abdominal infections, and urinary tract infections.
Polymyxin B can be administered through various routes depending on the infection. It is commonly given intravenously for systemic infections. For certain conditions, such as respiratory infections in patients with cystic fibrosis or skin infections, it can be administered via inhalation or topically, often in combination with other antibiotics. Its use is carefully managed due to potential side effects like kidney damage and neurological issues, requiring close patient monitoring.
How Bacteria Develop Resistance
Bacteria can develop resistance to polymyxin B primarily by altering the structure of their outer membrane, specifically the lipopolysaccharide (LPS). Since polymyxin B relies on its positive charge to bind to the negatively charged lipid A component of LPS, modifications to LPS can reduce this interaction.
A common mechanism involves the addition of positively charged residues, such as 4-amino-L-arabinose and phosphoethanolamine, to the lipid A molecule. These additions decrease the overall negative charge on the bacterial surface, thereby repelling the positively charged polymyxin B molecules and preventing effective binding.
Some bacteria can intrinsically produce LPS with these modifications, while others acquire the ability through mutations in genes that regulate LPS synthesis or through the transfer of resistance genes on plasmids. For instance, Acinetobacter baumannii can become highly resistant by spontaneously mutating genes involved in lipid A biosynthesis, leading to a complete lack of LPS or lipid A. Other less common resistance mechanisms include increased production of anionic capsular polysaccharides, expression of efflux pumps that actively remove the antibiotic, and alterations in outer membrane proteins.