biosynthetic process of antibacterial peptides active against Gram-negative bacteria

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of an antibacterial peptide with activity against Gram-negative bacteria. [GOC:add, PMID:11807545]

The biosynthesis of antibacterial peptides active against Gram-negative bacteria is a complex process that involves a series of intricate steps. These peptides, often referred to as antimicrobial peptides (AMPs), play a crucial role in the innate immune defense of various organisms.

**1. Gene Transcription and Translation:** The process begins with the transcription of the AMP gene into mRNA, which is then translated into a precursor peptide. This precursor often contains a signal peptide that directs the nascent peptide to the secretory pathway.

**2. Signal Peptide Cleavage:** The signal peptide is cleaved off during or after translocation across the membrane, yielding the mature AMP. This cleavage event is typically facilitated by specific proteases.

**3. Post-Translational Modifications:** Many AMPs undergo post-translational modifications that are crucial for their activity. These modifications can include:
* **Disulfide bond formation:** Disulfide bridges between cysteine residues can significantly influence the structure and stability of AMPs.
* **Glycosylation:** The addition of sugar moieties can enhance the activity and stability of some AMPs.
* **Proteolytic processing:** Some AMPs are further cleaved by specific proteases into their active forms.

**4. Assembly and Secretion:** Once modified, the AMPs are assembled into their final structure and secreted from the cell. In Gram-negative bacteria, this often involves the periplasmic space and the outer membrane.

**5. Mechanism of Action:** The mode of action of AMPs against Gram-negative bacteria is highly diverse, but generally involves disruption of bacterial membranes, interference with cell wall synthesis, and modulation of intracellular processes.

**6. Targeting Mechanisms:** Gram-negative bacteria have a unique outer membrane, which poses a significant challenge for AMPs. These peptides have evolved different strategies to overcome this barrier:
* **Direct interaction with the outer membrane:** Some AMPs can directly interact with the outer membrane, causing disruption and permeabilization.
* **Specific receptors:** Some AMPs bind to specific receptors on the bacterial surface, triggering an influx of ions or other cellular damage.
* **Porin channels:** Some AMPs can utilize existing porin channels in the outer membrane to gain access to the inner cell wall and cytoplasm.

**7. Resistance Mechanisms:** Gram-negative bacteria have developed various resistance mechanisms to counter the effects of AMPs. These include:
* **Mutation of target sites:** Altering the amino acid sequence of the bacterial cell wall or membrane components can reduce the efficacy of AMPs.
* **Production of efflux pumps:** Bacteria can use efflux pumps to actively expel AMPs from their cytoplasm.
* **Enzymatic inactivation:** Some bacteria produce enzymes that degrade AMPs, rendering them inactive.

The study of AMP biosynthesis and their interactions with Gram-negative bacteria is a rapidly evolving field with significant potential for developing new antibiotics to combat the rising threat of antibiotic resistance.'
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