Bacitracin is an antibiotic mixture derived from the bacterium Bacillus subtilis and sees frequent use in topical medicines to treat skin infections. First isolated in 1945, these compounds are produced by the bacterium through a process that does not involve ribosomes, known as nonribosomal peptide synthesis.
Core Structural Features of Bacitracin
The fundamental structure of bacitracin is a cyclic polypeptide. A polypeptide is a chain of amino acids, and in bacitracin, this chain is connected end-to-end to form a ring. This cyclic arrangement provides a stable framework for the molecule.
A defining characteristic of bacitracin’s architecture is the presence of a thiazoline ring. This feature results from a specific chemical modification. The thiazoline ring is formed through the condensation of two amino acids, isoleucine and cysteine, located at one end of the peptide. This modification is a part of the molecule’s overall shape.
The combination of the polypeptide ring and the attached thiazoline ring creates a distinct, lariat-shaped molecule. This structure possesses a degree of flexibility, allowing it to adopt different conformations in different chemical environments. The specific arrangement of its atoms is directly related to its biological function.
The Bacitracin A Isomer
Commercial bacitracin is a mixture of several closely related molecules, or isomers. Among these, Bacitracin A is the most abundant and exhibits the highest level of antibacterial activity. Other components, such as Bacitracin B1 and B2, are also present, but Bacitracin A is considered the principal active agent. The differences between these isomers lie in the specific amino acids at certain positions in their structures.
Bacitracin A is a dodecapeptide, composed of twelve amino acids. The sequence includes both D- and L-amino acid forms, which are mirror images of each other:
- L-cysteine
- D-glutamic acid
- L-leucine
- D-phenylalanine
- L-histidine
- D-aspartic acid
- L-asparagine
- D-ornithine
- L-lysine
- L-isoleucine
- Another L-isoleucine
The cyclic structure is formed when the side chain of the lysine amino acid links to the end of the peptide chain. This specific composition and arrangement are directly responsible for its potent biological effects.
Structure-Function Relationship
The antibiotic action of bacitracin is a direct result of its chemical structure. The cyclic nature of the polypeptide and the thiazoline ring enable it to bind with high specificity to a target molecule in bacteria called C55-isoprenyl pyrophosphate, also known as undecaprenyl pyrophosphate (UPP).
For this binding to occur, bacitracin requires a divalent metal ion, with zinc being particularly effective. The bacitracin molecule, a metal ion, and the UPP molecule form a stable ternary complex. In this complex, the bacitracin peptide wraps around the pyrophosphate head of the UPP molecule, effectively trapping it.
The primary role of UPP in bacteria is to transport the building blocks of the cell wall across the cell membrane. Specifically, it is a carrier in the synthesis of peptidoglycan, a polymer that gives the bacterial cell wall its structural integrity. By binding to UPP, bacitracin prevents a process called dephosphorylation, where a phosphate group is removed from UPP. This step is necessary to recycle the carrier so it can be used for another round of cell wall synthesis.
By interrupting this cycle, bacitracin halts the construction and repair of the bacterial cell wall, leading to cell lysis and death. The specificity of bacitracin for the UPP molecule makes it a targeted antibiotic, primarily affecting Gram-positive bacteria.
Structural Degradation and Stability
The chemical structure of bacitracin is susceptible to degradation, which can reduce its antibiotic activity. Environmental factors such as pH and temperature can induce changes in its molecular conformation. This instability is why bacitracin is most often used in topical applications rather than being administered internally.
A primary pathway for bacitracin’s inactivation involves deamidation. This reaction affects the asparagine residue within the polypeptide ring. Under certain conditions, this asparagine can be converted into aspartic acid, which alters the molecule’s overall structure and charge.
This chemical modification converts the highly active Bacitracin A into a much less potent form known as Bacitracin F. The change in the amino acid sequence disrupts the precise shape required for it to bind to its target. Consequently, the formation of the inactive Bacitracin F isomer leads to a significant loss of antibacterial efficacy.